4H-pyrrolo[3,2-c]pyridin-4-one derivatives

ABSTRACT

Compounds of formula (I) processes for their production and their use as pharmaceuticals.

This application is the U.S. national phase application, pursuant to 35U.S.C. § 371, of PCT International Application Serial No.:PCT/EP2018/078995, filed Oct. 23, 2018, designating the United Statesand published in English, which claims the benefit of the following U.S.Provisional Application No. 62/576,166, filed Oct. 24, 2017, the entirecontents of which are incorporated herein by reference.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Oct. 12, 2020, isnamed 167741_016702_US_SL.txt and is 37,837 bytes in size.

FIELD OF APPLICATION OF THE INVENTION

The invention relates to substituted 4H-pyrrolo[3,2-c]pyridin-4-onecompounds, a process for their production and uses thereof.

BACKGROUND OF THE INVENTION

The Epidermal Growth Factor Receptor (EGFR or EGF-receptor) receptortyrosine kinase family consists of 4 members: EGFR (Erbb1, Her1), ERBB2(Her2), ERBB3 (Her3), and ERBB4 (Her4). EGFR mediates activation of MAPKand PI3K signaling pathways and thereby regulates cell proliferation,differentiation, migration and survival. EGFR gene amplification,overexpression, and mutation are frequently observed in various cancerindications and are associated with a poor prognosis.

In lung adenocarcinoma, mutations of EGFR are prevalent in approximately15% of Western patients and up to 50% of East Asian patients. Thesemutations typically occur in one of four exons, exons 18-21, in thekinase domain of EGFR. The FDA-approved inhibitors gefitinib, erlotinib,and afatinib, targeting mutations in exons 18, 19, and 21 of EGFR, areeffective in patients but the response is often not durable. Resistancefrequently occurs in these patients in response to acquisition of asecond mutation, T790M. Second generation inhibitors, e.g. afatinib,irreversibly target this mutation but are still potent inhibitors ofwild-type EGFR. A third-generation irreversible inhibitor, osimertinib,that maximizes activity towards T790M while minimizing activity towardswild-type EGFR, is also effective in T790M mutant patients and iscurrently the standard treatment for T790M positive patients.

By contrast, and with the exception of A763_Y764insFQEA, small in-frameinsertions of EGFR exon 20 are resistant to available EGFR inhibitors atdoses achievable in lung cancer patients and comprise an unmet medicalneed.

Patients with EGFR exon 20 insertions, such as V769_770ins ASV andD770_N771ins SVD, show particular low response rates to all currentlyapproved EGFR-targeted therapies, resulting in significantly reducedprogression-free survival as well as overall survival. This has beenshown for the first-generation inhibitors erlotinib and gefitinib aswell as for the second-generation inhibitor afatinib. Therefore, thestandard treatment for EGFR exon 20 insertion patients is currentlychemotherapy.

Mutant EGFR is a promising drug target for cancer therapy. Inparticular, patients with primary resistance to approved anti-EGFRtherapies, due to EGFR exon 20 insertions, have only few treatmentoptions to date and there is a great need for novel alternative and/orimproved therapeutics to provide these patients with an efficacious,well-tolerable therapy.

Therefore, potent inhibitors of mutant EGFR, particularly of mutant EGFRwith exon 20 insertion mutations that show improved selectivity versuswild-type EGFR, represent valuable compounds that should complementtherapeutic options either as single agents or in combination with otherdrugs.

SUMMARY OF THE INVENTION

The invention provides compounds that inhibit a mutant EGFR (e.g., anEGFR comprising one or more exon 20 insertion mutations, etc.) and areselective for wild-type-EGFR.

It has now been found that the compounds of the present invention havesurprising and advantageous properties.

In particular, said compounds of the present invention have surprisinglybeen found to effectively inhibit mutant EGFR with exon 20 insertionmutations, particularly those harboring a D770_N771ins SVD exon 20insertion with an IC₅₀ below 5 nM. Furthermore it has been found thatthese compounds additionally show cellular potency below 1 μM in EGFRD770_N771ins SVD exon 20 insertion harboring BA/F3 cell lines.Surprisingly these compounds additionally show at least 5 foldselectivity in an antiproliferative assay of EGFR D770_N771ins SVD exon20 insertion harboring BA/F3 cell lines versus wild-type EGFR harboringBA/F3 cells. and may therefore be used for the treatment or prophylaxisof diseases of uncontrolled cell growth, proliferation and/or survival,inappropriate cellular immune responses, or inappropriate cellularinflammatory responses or diseases which are accompanied withuncontrolled cell growth, proliferation and/or survival, inappropriatecellular immune responses, or inappropriate cellular inflammatoryresponses mediated by mutant EGFR with exon 20 insertion mutationsand/or reduce (or block) proliferation in cells harboring EGFR exon 20insertion mutations, for example, haematological tumours, solid tumours,and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome,malignant lymphomas, head and neck tumours including brain tumours andbrain metastases, tumours of the thorax including non-small cell andsmall cell lung tumours, gastrointestinal tumours, endocrine tumours,mammary and other gynaecological tumours, urological tumours includingrenal, bladder and prostate tumours, skin tumours, and sarcomas, and/ormetastases thereof.

DESCRIPTION OF THE INVENTION

In accordance with a first aspect, the invention relates to compounds offormula (I),

in which:

-   R¹ represents methyl, ethyl, trifluoromethyl, 2,2-difluoroethyl,    cyano, bromo, methoxy, or difluoromethoxy, or    -   with the proviso that when R¹ is chloro, then R² represents        hydrogen or chloro and R³ and R⁴ represent hydrogen;-   R² represents hydrogen, methyl, fluoro, chloro or bromo;-   R³ represents hydrogen or fluoro;-   R⁴ represents hydrogen or fluoro, wherein at least one of R³ and R⁴    represents hydrogen;-   R⁵ represents C₂-C₅-alkyl,    -   which is substituted once with hydroxy, C₁-C₄-alkoxy, R⁷R⁸N—, or        phenyl, or R⁶—CH₂—,    -   wherein said phenyl groups are optionally substituted one or        more times, independently of each other, with R′;-   R′ represents, independently of each other, hydroxy, halogen, cyano,    C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl or C₁-C₄-haloalkoxy;-   R⁶ represents a group selected from the group:

-   -   wherein * indicates the point of attachment of said group with        the rest of the molecule;

-   R⁷, R⁸ represent, independently of each other, C₁-C₃-alkyl,    C₁-C₃-haloalkyl or

-   R⁷ and R⁸ together with the nitrogen atom to which they are attached    form a 5- to 6-membered nitrogen containing heterocyclic ring,    optionally containing one additional heteroatom or heteroatom    containing group selected from O and NR¹⁰;

-   R⁹ represents hydrogen, C₁-C₃-alkyl or C₁-C₃-haloalkyl;

-   R¹⁰ represents hydrogen or C₁-C₃-alkyl;    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer or stereoisomer.

In a second aspect, the invention relates to compounds of formula (I) asdescribed supra, wherein

-   R¹ represents methyl, ethyl, trifluoromethyl, 2,2-difluoroethyl,    cyano, bromo, methoxy, or difluoromethoxy, or    -   with the proviso that when R¹ is chloro, then R² represents        chloro;-   R² represents fluoro or chloro;-   R³ represents hydrogen;-   R⁴ represents hydrogen;-   R⁵ represents C₂-C₅-alkyl,    -   which is substituted once with hydroxy, C₁-C₂-alkoxy or R⁷R⁸N—,        or R⁶—CH₂—;-   R⁶ represents a group selected from the group:

-   -   wherein * indicates the point of attachment of said group with        the rest of the molecule;

-   R⁷, R⁸ represent, independently of each other, C₁-C₂-alkyl, or    C₁-C₂-haloalkyl;

-   R⁹ represents hydrogen, C₁-C₂-alkyl or C₁-C₂-haloalkyl;    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer or stereoisomer.

In a third aspect, the invention relates to compounds of formula (I) asdescribed supra, wherein:

-   R¹ represents methyl, ethyl, trifluoromethyl, 2,2-difluoroethyl,    cyano, bromo, methoxy, or difluoromethoxy, or    -   with the proviso that when R¹ is chloro, then R² represents        chloro;-   R² represents fluoro or chloro;-   R³ represents hydrogen;-   R⁴ represents hydrogen;-   R⁵ represents C₄-C₅-alkyl,    -   which is substituted once with hydroxy, methoxy or R⁷R⁸N—, or        R⁶—CH₂—;-   R⁶ represents a group selected from the group:

-   -   wherein * indicates the point of attachment of said group with        the rest of the molecule;

-   is R⁷, R⁸ represent, independently of each other, methyl, or    C₁-C₂-fluoroalkyl;

-   R⁹ represents C₁-C₂-alkyl or C₁-C₂-fluoroalkyl;    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer or stereoisomer.

In a fourth aspect, the invention relates to compounds of formula (I),

in which:

-   X represents CR^(1a);-   R^(1a) represents, independently of each other, hydrogen, hydroxy,    halogen, cyano, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl or    C₁-C₄-haloalkoxy;-   R^(1b) represents, independently of each other, hydroxy, halogen,    cyano, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl or    C₁-C₄-haloalkoxy;-   R^(1c) represents, independently of each other, hydroxy, halogen,    cyano, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl or    C₁-C₄-haloalkoxy;-   R² represents C₁-C₆-alkyl    -   which is optionally substituted one, two or three times,        independently of each other, with halogen and is optionally        substituted one time with hydroxy, C₁-C₄-alkoxy, R³R⁴N—,        C₃-C₆-cycloalkyl, 5- to 6-membered heterocycloalkyl or phenyl,    -   wherein C₃-C₆-cycloalkyl, 5- to 6-membered heterocycloalkyl and        phenyl groups are optionally substituted one or more times,        independently of each other, with R^(1c);-   R³, R⁴ represent, independently of each other, hydrogen or    C₁-C₄-alkyl, or-   R³ and R⁴ together with the nitrogen atom to which they are attached    form a 5- to 6-membered nitrogen containing heterocyclic ring,    optionally containing one additional heteroatom or heteroatom    containing group selected from O, NR⁵ and S;-   R⁵ represents hydrogen, C₁-C₄-alkyl, C₃-C₆-cycloalkyl,    C₁-C₄-haloalkyl;-   n represents 0, 1, 2 or 3;    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer or stereoisomer.

In a fifth aspect, the invention relates to compounds of formula (I) asdescribed supra, which is selected from the group consisting of:

-   2-[3-(2-methoxyethoxy)pyridin-4-yl]-3-(phenylamino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   2-[3-(3,3-dimethylbutoxy)pyridin-4-yl]-3-[(3-fluorophenyl)amino]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   2-[3-(benzyloxy)pyridin-4-yl]-3-[(3-fluorophenyl)amino]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-[(3-fluorophenyl)amino]-2-[3-(2-hydroxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   2-{3-[2-(dimethylamino)ethoxy]pyridin-4-yl}-3-[(3-fluorophenyl)amino]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-[(3-fluorophenyl)amino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-[(3-fluorophenyl)amino]-2-{3-[2-methyl-2-(morpholin-4-yl)propoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-[(3-fluorophenyl)amino]-2-(3-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-[(3,5-difluorophenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-[(3,5-difluorophenyl)amino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-{[2-(difluoromethoxy)phenyl]amino}-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-[(2-bromo-3-fluorophenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   2-[3-(2-methoxyethoxy)pyridin-4-yl]-3-[(2-methoxyphenyl)amino]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   2-[3-(2-methoxyethoxy)pyridin-4-yl]-3-{[2-(trifluoromethoxy)phenyl]amino}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-{[2-(2,2-difluoroethyl)phenyl]amino}-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-[(3-fluoro-2-methoxyphenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-[(3-fluoro-2-methoxyphenyl)amino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-{[2-(difluoromethoxy)-3-fluorophenyl]amino}-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-{[2-(difluoromethoxy)-3-fluorophenyl]amino}-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-[(3-fluoro-2-methylphenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-[(3-fluoro-2-methylphenyl)amino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-{[2-(2,2-difluoroethyl)-3-fluorophenyl]amino}-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-{[2-(2,2-difluoroethyl)-3-fluorophenyl]amino}-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-[(3-fluoro-2-hydroxyphenyl)amino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-[(2-ethoxy-3-fluorophenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-[(2-ethoxy-3-fluorophenyl)amino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-{[2-(2,2-difluoroethoxy)-3-fluorophenyl]amino}-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-[(3,4-difluoro-2-methoxyphenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-[(3,4-difluoro-2-methoxyphenyl)amino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,-   3-[(3,5-difluoro-2-methoxyphenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,    and-   3-[(3,5-difluoro-2-methoxyphenyl)amino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one,    or an N-oxide, a salt, a tautomer or a stereoisomer of said    compound, or a salt of said N-oxide, tautomer or stereoisomer.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R¹ represents methyl, trifluoromethyl, 2,2-difluoroethyl, cyano,    bromo, methoxy, difluoromethoxy, or    -   with the proviso that when R¹ is chloro, then R² represents        hydrogen or chloro and R³ and R⁴ represent hydrogen.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R¹ represents methyl, trifluoromethyl, 2,2-difluoroethyl, cyano,    bromo, methoxy, difluoromethoxy, or    -   with the proviso that when R¹ is chloro, then R² represents        chloro.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R² represents hydrogen, fluoro or chloro.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R² represents fluoro or chloro.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R³ represents hydrogen or fluoro.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R³ represents hydrogen.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R⁴ represents hydrogen or fluoro, wherein at least one of R³ and R⁴    represents hydrogen.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R⁴ represents hydrogen.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R⁵ represents C₂-C₅-alkyl,    -   which is substituted once with hydroxy, C₁-C₄-alkoxy, R⁷R⁸N- or        phenyl, or R⁶—CH₂—,    -   wherein said phenyl groups are optionally substituted one or        more times, independently of each other, with R′.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R⁵ represents C₂-C₅-alkyl, which is substituted once with hydroxy,    C₁-C₄-alkoxy, R⁷R⁸N- or phenyl,    -   wherein said phenyl groups are optionally substituted one or        more times, independently of each other, with R′.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R⁵ represents C₂-C₅-alkyl,    -   which is substituted once with hydroxy, C₁-C₄-alkoxy, R⁷R⁸N- or        phenyl, or R⁶—CH₂—.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R⁵ represents C₂-C₅-alkyl,    -   which is substituted once with hydroxy, C₁-C₂-alkoxy or R⁷R⁸N—,        or R⁶—CH₂—.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R⁵ represents C₄-C₅-alkyl,    -   which is substituted once with hydroxy, methoxy or R⁷R⁸N—, or        R⁶—CH₂—.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R⁵ represents C₄-C₅-alkyl, which is substituted once with hydroxy,    methoxy or R⁷R⁸N—.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R⁵ represents R⁶—CH₂—.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R⁶ represents a group selected from the group:

-   -   wherein * indicates the point of attachment of said group with        the rest of the molecule.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R⁶ represents a group selected from the group:

-   -   wherein * indicates the point of attachment of said group with        the rest of the molecule.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R⁷, R⁸ represent, independently of each other, C₁-C₃-alkyl,    C₁-C₃-haloalkyl or-   R⁷ and R⁸ together with the nitrogen atom to which they are attached    form a 5- to 6-membered nitrogen containing heterocyclic ring,    optionally containing one additional heteroatom or heteroatom    containing group selected from O and NR¹⁰.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   is R⁷, R⁸ represent, independently of each other, C₁-C₂-alkyl, or    C₁-C₂-haloalkyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R⁷, R⁸ represent, independently of each other, methyl, or    C₁-C₂-fluoroalkyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R⁹ represents hydrogen, C₁-C₃-alkyl or C₁-C₃-haloalkyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R⁹ represents hydrogen, C₁-C₂-alkyl or C₁-C₂-haloalkyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R⁹ represents C₁-C₂-alkyl or C₁-C₂-fluoroalkyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R¹⁰ represents hydrogen or C₁-C₃-alkyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R¹⁰ represents hydrogen or methyl.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R′ represents, independently of each other, hydroxy, halogen, cyano,    C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl or C₁-C₄-haloalkoxy.

In a further embodiment of the above-mentioned aspects, the inventionrelates to compounds of formula (I), wherein:

-   R′ represents, independently of each other, hydroxy, fluoro, chloro,    cyano, methyl, methoxy, trifluoromethyl or trifluoromethoxy.

A further aspect of the invention relates to compounds of formula (I),which are present as their salts.

It is to be understood that the present invention relates to anysub-combination within any embodiment or aspect of the present inventionof compounds of general formula (I), supra.

More particularly still, the present invention covers compounds ofgeneral formula (I) which are disclosed in the Example section of thistext, infra.

In accordance with another aspect, the present invention covers methodsof preparing compounds of the present invention, said methods comprisingthe steps as described in the Experimental Section herein.

Another embodiment of the invention are compounds according to theclaims as disclosed in the Claims section wherein the definitions aredefined according to the preferred or more preferred definitions asdisclosed below or specifically disclosed residues of the exemplifiedcompounds and subcombinations thereof.

Definitions

It is to be understood that embodiments disclosed herein are not meantto be understood as individual embodiments which would not relate to oneanother. Features discussed with one embodiment or aspect of theinvention are meant to be disclosed also in connection with otherembodiments or aspects of the invention shown herein. If, in one case, aspecific feature is not disclosed with one embodiment or aspect of theinvention, but with another, the skilled person would understand thatdoes not necessarily mean that said feature is not meant to be disclosedwith said other embodiment or aspect of the invention. The skilledperson would understand that it is the gist of this application todisclose said feature also for the other embodiment or aspect of theinvention, but that just for purposes of clarity and to keep the lengthof this specification manageable. For example, it is to be understoodthat all aspects, embodiments, pharmaceutical compositions,combinations, uses and/or methods of the present invention definedherein for the compounds of formula (I) also relate to more specificembodiments of the compounds of formula (I), such as, but not limitedto, the compounds of formula (Ia) and vice-versa, for example.

It is further to be understood that the content of the prior artdocuments referred to herein is incorporated by reference in theirentirety, e.g., for enablement purposes, namely when e.g. a method isdiscussed details of which are described in said prior art document.This approach serves to keep the length of this specificationmanageable.

Constituents which are optionally substituted as stated herein, may besubstituted, unless otherwise noted, one or more times, independently ofone another at any possible position. When any variable occurs more thanone time in any constituent, each definition is independent. Forexample, when R¹, R^(1a), R^(1b), R^(1c), R², R³ and/or R⁴ occur morethan one time in any compound of formula (I) each definition of R¹,R^(1a), R^(1b), R^(1c), R², R³ and R⁴ is independent.

Should a constituent be composed of more than one part, e.g.C₁-C₄-alkoxy-C2-C₄-alkyl, the position of a possible substituent can beat any of these parts at any suitable position.

A hyphen at the beginning or at the end of the constituent marks thepoint of attachment to the rest of the molecule. Should a ring besubstituted the substitutent could be at any suitable position of thering, also on a ring nitrogen atom, if suitable.

The term “comprising” when used in the specification includes“consisting of”.

If it is referred to “as mentioned above” or “mentioned above”, “supra”within the description it is referred to any of the disclosures madewithin the specification in any of the preceding pages.

If it is referred to “as mentioned herein”, “described herein”,“provided herein” or “stated herein” within the description it isreferred to any of the disclosures made within the specification in anyof the preceding or subsequent pages.

“Suitable” within the sense of the invention means chemically possibleto be made by methods within the knowledge of a skilled person.

The terms as mentioned in the present text have preferably the followingmeanings:

The term “halogen atom”, “halo-” or “Hal-” is to be understood asmeaning a fluorine, chlorine, bromine or iodine atom.

The term “C₁-C₆-alkyl” is to be understood as meaning a linear orbranched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5,or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl,iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, 2-methylbutyl,1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl,1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl,1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl,2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl,1,3-dimethylbutyl or 1,2-dimethylbutyl group, or an isomer thereof.Particularly, said group has 1, 2, 3 or 4 carbon atoms (“C₁-C₄-alkyl”),e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl,tert-butyl group, more particularly 1, 2 or 3 carbon atoms(“C₁-C₃-alkyl”), e.g. a methyl, ethyl, n-propyl or iso-propyl group.

The term “C₁-C₄-haloalkyl” is to be understood as meaning a linear orbranched, saturated, monovalent hydrocarbon group in which the term“C₁-C₄-alkyl” is defined supra, and in which one or more hydrogen atomsis replaced by a halogen atom, in identically or differently, i.e. onehalogen atom being independent from another. Particularly, said halogenatom is F. Said C₁-C₄-haloalkyl group is, for example, —CF₃, —CHF₂,—CH₂F, —CF₂CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂CH₂CF₃, or —CH(CH₂F)₂.

The term “C₁-C₄-alkoxy” is to be understood as meaning a linear orbranched, saturated, monovalent, hydrocarbon group of formula —O-alkyl,in which the term “alkyl” is defined supra, e.g. a methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy or sec-butoxygroup, or an isomer thereof.

Unless defined otherwise, the term “5- to 6-membered heterocycloalkyl”or “5- to 6-membered heterocyclic ring”, is to be understood as meaninga saturated, monovalent, monocyclic hydrocarbon ring which contains 4 or5 carbon atoms, and one heteroatom-containing group selected from O andNR, wherein R means a hydrogen atom, a C₁-C₃-alkyl or a C₁-C₃-haloalkylgroup, it being possible for said heterocycloalkyl group to be attachedto the rest of the molecule via any one of the carbon atoms.

Particularly, without being limited thereto, said heterocycloalkyl canbe a 5-membered ring, such as tetrahydrofuranyl, pyrazolidinyl, or a6-membered ring, such as tetrahydropyranyl, piperidinyl, for example.

The term “C₁-C₆”, as used throughout this text, e.g. in the context ofthe definition of “C₁-C₆-alkyl” or “C₁-C₆-haloalkyl” is to be understoodas meaning an alkyl group having a finite number of carbon atoms of 1 to6, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms. It is to be understood furtherthat said term “C₁-C₆” is to be interpreted as any sub-range comprisedtherein, e.g. C₁-C₆, C₂-C₆, C₃-C₆, C₁-C₂, C₁-C₃, particularly C₁-C₂,C₁-C₃, C₁-C₄.

The term “C₁-C₄”, as used throughout this text, e.g. in the context ofthe definition of “C₁-C₄-alkyl”, “C₁-C₄-haloalkyl”, “C₁-C₄-alkoxy”, or“C₁-C₄-haloalkoxy” is to be understood as meaning an alkyl group havinga finite number of carbon atoms of 1 to 4, i.e. 1, 2, 3 or 4 carbonatoms. It is to be understood further that said term “C₁-C₄” is to beinterpreted as any sub-range comprised therein, e.g. C₁-C₄, C₂-C₄,C₃-C₄, C₁-C₂, C₁-C₃, particularly C₁-C₂, C₁-C₃, C₁-C₄, in the case of“C₁-C₆-haloalkyl” or “C₁-C₄-haloalkoxy” even more particularly C₁-C₂.

Further, as used herein, the term “C₃-C₆”, as used throughout this text,e.g. in the context of the definition of “C₃-C₆-cycloalkyl”, is to beunderstood as meaning a cycloalkyl group having a finite number ofcarbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to beunderstood further that said term “C₃-C₆” is to be interpreted as anysub-range comprised therein, e.g. C₃-C₆, C₄-C₅, C₃-C₅, C₃-C₄, C₄-C₆,C₅-C₆; particularly C₃-C₆.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

Ring system substituent means a substituent attached to an aromatic ornonaromatic ring system which, for example, replaces an availablehydrogen on the ring system.

As used herein, the term “one or more”, e.g. in the definition of thesubstituents of the compounds of the general formulae of the presentinvention, is understood as meaning “one, two, three, four or five,particularly one, two, three or four, more particularly one, two orthree, even more particularly one or two”.

The compounds of general formula (I) may exist as isotopic variants. Theinvention therefore includes one or more isotopic variant(s) of thecompounds of general formula (I), particularly deuterium-containingcompounds of general formula (I).

The term “Isotopic variant” of a compound or a reagent is defined as acompound exhibiting an unnatural proportion of one or more of theisotopes that constitute such a compound.

The term “Isotopic variant of the compound of general formula (I)” isdefined as a compound of general formula (I) exhibiting an unnaturalproportion of one or more of the isotopes that constitute such acompound.

The expression “unnatural proportion” is to be understood as meaning aproportion of such isotope which is higher than its natural abundance.The natural abundances of isotopes to be applied in this context aredescribed in “Isotopic Compositions of the Elements 1997”, Pure Appl.Chem., 70(1), 217-235, 1998. Examples of such isotopes include stableand radioactive isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ²H(deuterium), ³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S,³⁴S, ³⁵S, ³⁶S, ¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁵I, ¹²⁹I and ¹³¹I,respectively.

With respect to the treatment and/or prophylaxis of the disordersspecified herein the isotopic variant(s) of the compounds of generalformula (I) in one embodiment contain deuterium (“deuterium-containingcompounds of general formula (I)”). Isotopic variants of the compoundsof general formula (I) in which one or more radioactive isotopes, suchas ³H or ¹⁴C, are incorporated are useful e.g. in drug and/or substratetissue distribution studies. These isotopes are particularly preferredfor the ease of their incorporation and detectability. Positron emittingisotopes such as ¹⁸F or ¹¹C may be incorporated into a compound ofgeneral formula (I). These isotopic variants of the compounds of generalformula (I) are useful for in vivo imaging applications.Deuterium-containing and ¹³C-containing compounds of general formula (I)can be used in mass spectrometry analyses (H. J. Leis et al., Curr. Org.Chem., 1998, 2, 131) in the context of preclinical or clinical studies.

Isotopic variants of the compounds of general formula (I) can generallybe prepared by methods known to a person skilled in the art, such asthose described in the schemes and/or examples herein, by substituting areagent for an isotopic variant of said reagent, in one embodiment for adeuterium-containing reagent. Depending on the desired sites ofdeuteration, in some cases deuterium from D₂O can be incorporated eitherdirectly into the compounds or into reagents that are useful forsynthesizing such compounds (Esaki et al., Tetrahedron, 2006, 62, 10954;Esaki et al., Chem. Eur. J., 2007, 13, 4052). Deuterium gas is also auseful reagent for incorporating deuterium into molecules. Catalyticdeuteration of olefinic bonds (H. J. Leis et al., Curr. Org. Chem.,1998, 2, 131; J. R. Morandi et al., J. Org. Chem., 1969, 34 (6), 1889)and acetylenic bonds (N. H. Khan, J. Am. Chem. Soc., 1952, 74 (12),3018; S. Chandrasekhar et al., Tetrahedron, 2011, 52, 3865) is a rapidroute for incorporation of deuterium. Metal catalysts (i.e. Pd, Pt, andRh) in the presence of deuterium gas can be used to directly exchangedeuterium for hydrogen in functional groups containing hydrocarbons (J.G. Atkinson et al., U.S. Pat. No. 3,966,781). A variety of deuteratedreagents and synthetic building blocks are commercially available fromcompanies such as for example C/D/N Isotopes, Quebec, Canada; CambridgeIsotope Laboratories Inc., Andover, Mass., USA; and CombiPhos Catalysts,Inc., Princeton, N.J., USA. Further information on the state of the artwith respect to deuterium-hydrogen exchange is given for example inHanzlik et al., J. Org. Chem. 55, 3992-3997, 1990; R. P. Hanzlik et al.,Biochem. Biophys. Res. Commun. 160, 844, 1989; P. J. Reider et al., J.Org. Chem. 52, 3326-3334, 1987; M. Jarman et al., Carcinogenesis 16(4),683-688, 1993; J. Atzrodt et al., Angew. Chem., Int. Ed. 2007, 46, 7744;K. Matoishi et al., J. Chem. Soc, Chem. Commun. 2000, 1519-1520; K.Kassahun et al., WO2012/112363.

The term “deuterium-containing compound of general formula (I)” isdefined as a compound of general formula (I), in which one or morehydrogen atom(s) is/are replaced by one or more deuterium atom(s) and inwhich the abundance of deuterium at each deuterated position of thecompound of general formula (I) is higher than the natural abundance ofdeuterium, which is about 0.015%. Particularly, in adeuterium-containing compound of general formula (I) the abundance ofdeuterium at each deuterated position of the compound of general formula(I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, in oneembodiment higher than 90%, 95%, 96% or 97%, in other embodiments higherthan 98% or 99% at said position(s). It is understood that the abundanceof deuterium at each deuterated position is independent of the abundanceof deuterium at other deuterated position(s).

The selective incorporation of one or more deuterium atom(s) into acompound of general formula (I) may alter the physicochemical properties(such as for example acidity [A. Streitwieser et al., J. Am. Chem. Soc.,1963, 85, 2759; C. L. Perrin, et al., J. Am. Chem. Soc., 2007, 129,4490], basicity [C. L. Perrin, et al., J. Am. Chem. Soc., 2003, 125,15008; C. L. Perrin in Advances in Physical Organic Chemistry, 44, 144;C. L. Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity[B. Testa et al., Int. J. Pharm., 1984, 19(3), 271]) and/or themetabolic profile of the molecule and may result in changes in the ratioof parent compound to metabolites or in the amounts of metabolitesformed. Such changes may result in certain therapeutic advantages andhence may be preferred in some circumstances. Reduced rates ofmetabolism and metabolic switching, where the ratio of metabolites ischanged, have been reported (D. J. Kushner et al., Can. J. Physiol.Pharmacol., 1999, 77, 79; A. E. Mutlib et al., Toxicol. Appl.Pharmacol., 2000, 169, 102). These changes in the exposure to parentdrug and metabolites can have important consequences with respect to thepharmacodynamics, tolerability and efficacy of a deuterium-containingcompound of general formula (I). In some cases deuterium substitutionreduces or eliminates the formation of an undesired or toxic metaboliteand enhances the formation of a desired metabolite (e.g. Nevirapine: A.M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Uetrecht et al.,Chemical Research in Toxicology, 2008, 21, 9, 1862; Efavirenz: A. E.Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In othercases the major effect of deuteration is to reduce the rate of systemicclearance. As a result, the biological half-life of the compound isincreased. The potential clinical benefits would include the ability tomaintain similar systemic exposure with decreased peak levels andincreased trough levels. This could result in lower side effects andenhanced efficacy, depending on the particular compound'spharmacokinetic/pharmacodynamic relationship. Indiplon (A. J. Morales etal., Abstract 285, The 15^(th) North American Meeting of theInternational Society of Xenobiotics, San Diego, Calif., Oct. 12-16,2008), ML-337 (C. J. Wenthur et al., J. Med. Chem., 2013, 56, 5208), andOdanacatib (K. Kassahun et al., WO2012/112363) are examples for thisdeuterium effect. Still other cases have been reported in which reducedrates of metabolism result in an increase in exposure of the drugwithout changing the rate of systemic clearance (e.g. Rofecoxib: F.Schneider et al., Arzneim. Forsch. Drug. Res., 2006, 56, 295;Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993).Deuterated drugs showing this effect may have reduced dosingrequirements (e.g. lower number of doses or lower dosage to achieve thedesired effect) and/or may produce lower metabolite loads.

A compound of general formula (I) may have multiple potential sites ofattack for metabolism. To optimize the above-described effects onphysicochemical properties and metabolic profile, deuterium-containingcompounds of general formula (I) having a certain pattern of one or moredeuterium-hydrogen exchange(s) can be selected. Particularly, thedeuterium atom(s) of deuterium-containing compound(s) of general formula(I) is/are attached to a carbon atom and/or is/are located at thosepositions of the compound of general formula (I), which are sites ofattack for metabolizing enzymes such as e.g. cytochrome P450.

Where the plural form of the word compounds, salts, polymorphs,hydrates, solvates and the like, is used herein, this is taken to meanalso a single compound, salt, polymorph, isomer, hydrate, solvate or thelike.

By “stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The compounds of this invention may contain one or more asymmetriccentre, depending upon the location and nature of the varioussubstituents desired. Asymmetric carbon atoms may be present in the (R)or (S) configuration, resulting in racemic mixtures in the case of asingle asymmetric centre, and diastereomeric mixtures in the case ofmultiple asymmetric centres. In certain instances, asymmetry may also bepresent due to restricted rotation about a given bond, for example, thecentral bond adjoining two substituted aromatic rings of the specifiedcompounds.

Substituents on a ring may also be present in either cis or trans form.It is intended that all such configurations (including enantiomers anddiastereomers), are included within the scope of the present invention.

Preferred compounds are those which produce the more desirablebiological activity. Separated, pure or partially purified isomers andstereoisomers or racemic or diastereomeric mixtures of the compounds ofthis invention are also included within the scope of the presentinvention. The purification and the separation of such materials can beaccomplished by standard techniques known in the art.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, ditoluoyltartaric andcamphorsulfonic acid. Mixtures of diastereoisomers can be separated intotheir individual diastereomers on the basis of their physical and/orchemical differences by methods known in the art, for example, bychromatography or fractional crystallisation. The optically active basesor acids are then liberated from the separated diastereomeric salts. Adifferent process for separation of optical isomers involves the use ofchiral chromatography (e.g., chiral HPLC columns), with or withoutconventional derivatisation, optimally chosen to maximise the separationof the enantiomers. Suitable chiral HPLC columns are manufactured byDaicel, e.g., Chiracel OD and Chiracel OJ among many others, allroutinely selectable. Enzymatic separations, with or withoutderivatisation, are also useful. The optically active compounds of thisinvention can likewise be obtained by chiral syntheses utilizingoptically active starting materials.

In order to limit different types of isomers from each other referenceis made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

The present invention includes all possible stereoisomers of thecompounds of the present invention as single stereoisomers, or as anymixture of said stereoisomers, e.g. R- or S-isomers, or E- or Z-isomers,in any ratio. Isolation of a single stereoisomer, e.g. a singleenantiomer or a single diastereomer, of a compound of the presentinvention may be achieved by any suitable state of the art method, suchas chromatography, especially chiral chromatography, for example.

Further, the compounds of the present invention may exist as tautomers.For example, any compound of the present invention which contains apyrazole moiety as a heteroaryl group for example can exist as a 1Htautomer, or a 2H tautomer, or even a mixture in any amount of the twotautomers, or a triazole moiety for example can exist as a 1H tautomer,a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said1H, 2H and 4H tautomers, namely:

The present invention includes all possible tautomers of the compoundsof the present invention as single tautomers, or as any mixture of saidtautomers, in any ratio.

Further, the compounds of the present invention can exist as N-oxides,which are defined in that at least one nitrogen of the compounds of thepresent invention is oxidised. The present invention includes all suchpossible N-oxides.

The present invention also relates to useful forms of the compounds asdisclosed herein, such as metabolites, hydrates, solvates, prodrugs,salts, in particular pharmaceutically acceptable salts, andco-precipitates.

The compounds of the present invention can exist as a hydrate, or as asolvate, wherein the compounds of the present invention contain polarsolvents, in particular water, methanol or ethanol for example asstructural element of the crystal lattice of the compounds. The amountof polar solvents, in particular water, may exist in a stoichiometric ornon-stoichiometric ratio. In the case of stoichiometric solvates, e.g. ahydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc.solvates or hydrates, respectively, are possible. The present inventionincludes all such hydrates or solvates.

Further, the compounds of the present invention can exist in free form,e.g. as a free base, or as a free acid, or as a zwitterion, or can existin the form of a salt. Said salt may be any salt, either an organic orinorganic addition salt, particularly any pharmaceutically acceptableorganic or inorganic addition salt, customarily used in pharmacy.

The term “pharmaceutically acceptable salt” refers to a relativelynon-toxic, inorganic or organic acid addition salt of a compound of thepresent invention. For example, see S. M. Berge, et al. “PharmaceuticalSalts,” J. Pharm. Sci. 1977, 66, 1-19.

A suitable pharmaceutically acceptable salt of the compounds of thepresent invention may be, for example, an acid-addition salt of acompound of the present invention bearing a nitrogen atom, in a chain orin a ring, for example, which is sufficiently basic, such as anacid-addition salt with an inorganic acid, such as hydrochloric,hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric or nitricacid, for example, or with an organic acid, such as formic, acetic,acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic,heptanoic, undecanoic, lauric, benzoic, salicylic,2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic,cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic,pamoic, pectinic, persulfuric, 3-phenylpropionic, picric, pivalic,2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic,dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic,methansulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic,camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic,malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic,mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic,sulfosalicylic, hemisulfuric orthiocyanic acid, for example.

Further, another suitably pharmaceutically acceptable salt of a compoundof the present invention which is sufficiently acidic, is an alkalimetal salt, for example a sodium or potassium salt, an alkaline earthmetal salt, for example a calcium or magnesium salt, an ammonium salt ora salt with an organic base which affords a physiologically acceptablecation, for example a salt with N-methyl-glucamine, dimethyl-glucamine,ethyl-glucamine, lysine, dicyclohexylamine, 1,6-hexadiamine,ethanolamine, glucosamine, sarcosine, serinol,tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base,1-amino-2,3,4-butantriol. Additionally, basic nitrogen containing groupsmay be quaternised with such agents as lower alkyl halides such asmethyl, ethyl, propyl, and butyl chlorides, bromides and iodides;dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamylsulfates, long chain halides such as decyl, lauryl, myristyl and stearylchlorides, bromides and iodides, aralkyl halides like benzyl andphenethyl bromides and others.

Those skilled in the art will further recognise that acid addition saltsof the claimed compounds may be prepared by reaction of the compoundswith the appropriate inorganic or organic acid via any of a number ofknown methods. Alternatively, alkali and alkaline earth metal salts ofacidic compounds of the invention are prepared by reacting the compoundsof the invention with the appropriate base via a variety of knownmethods.

The present invention includes all possible salts of the compounds ofthe present invention as single salts, or as any mixture of said salts,in any ratio.

In the present text, in particular in the Experimental Section, for thesynthesis of intermediates and of examples of the present invention,when a compound is mentioned as a salt form with the corresponding baseor acid, the exact stoichiometric composition of said salt form, asobtained by the respective preparation and/or purification process, is,in most cases, unknown.

Unless specified otherwise, suffixes to chemical names or structuralformulae such as “hydrochloride”, “trifluoroacetate”, “sodium salt”, or“x HCl”, “x CF₃COOH”, “x Na⁺”, for example, are to be understood as nota stoichiometric specification, but solely as a salt form.

This applies analogously to cases in which synthesis intermediates orexample compounds or salts thereof have been obtained, by thepreparation and/or purification processes described, as solvates, suchas hydrates with (if defined) unknown stoichiometric composition.

The salts include water-insoluble and, particularly, water-solublesalts.

Furthermore, derivatives of the compounds of formula (I) and the saltsthereof which are converted into a compound of formula (I) or a saltthereof in a biological system (bioprecursors or pro-drugs) are coveredby the invention. Said biological system is e.g. a mammalian organism,particularly a human subject. The bioprecursor is, for example,converted into the compound of formula (I) or a salt thereof bymetabolic processes.

As used herein, the term “in vivo hydrolysable ester” is understood asmeaning an in vivo hydrolysable ester of a compound of the presentinvention containing a carboxy or hydroxy group, for example, apharmaceutically acceptable ester which is hydrolysed in the human oranimal body to produce the parent acid or alcohol. Suitablepharmaceutically acceptable esters for carboxy include for examplealkyl, cycloalkyl and optionally substituted phenylalkyl, in particularbenzyl esters, C₁-C₆ alkoxymethyl esters, e.g. methoxymethyl, C₁-C₆alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters,C₃-C₈ cycloalkoxy-carbonyloxy-C₁-C₆ alkyl esters, e.g.1-cyclohexylcarbonyloxyethyl, 1,3-dioxolen-2-onylmethyl esters, e.g.5-methyl-1,3-dioxolen-2-onylmethyl, and C₁-C₆-alkoxycarbonyloxyethylesters, e.g. 1-methoxycarbonyloxyethyl, and may be formed at any carboxygroup in the compounds of this invention.

An in vivo hydrolysable ester of a compound of the present inventioncontaining a hydroxy group includes inorganic esters such as phosphateesters and [alpha]-acyloxyalkyl ethers and related compounds which as aresult of the in vivo hydrolysis of the ester breakdown to give theparent hydroxy group. Examples of [alpha]-acyloxyalkyl ethers includeacetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of invivo hydrolysable ester forming groups for hydroxy include alkanoyl,benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl,alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl. The present invention covers allsuch esters.

Furthermore, the present invention includes all possible crystallineforms, or polymorphs, of the compounds of the present invention, eitheras single polymorphs, or as a mixture of more than one polymorphs, inany ratio.

In the context of the properties of the compounds of the presentinvention the term “pharmacokinetic profile” means one single parameteror a combination thereof including permeability, bioavailability,exposure, and pharmacodynamic parameters such as duration, or magnitudeof pharmacological effect, as measured in a suitable experiment.Compounds with improved pharmacokinetic profiles can, for example, beused in lower doses to achieve the same effect, may achieve a longerduration of action, or a may achieve a combination of both effects.

The term “combination” in the present invention is used as known topersons skilled in the art and may be present as a fixed combination, anon-fixed combination or kit-of-parts.

A “fixed combination” in the present invention is used as known topersons skilled in the art and is defined as a combination wherein thesaid first active ingredient and the said second active ingredient arepresent together in one unit dosage or in a single entity. One exampleof a “fixed combination” is a pharmaceutical composition wherein thesaid first active ingredient and the said second active ingredient arepresent in admixture for simultaneous administration, such as in aformulation. Another example of a “fixed combination” is apharmaceutical combination wherein the said first active ingredient andthe said second active ingredient are present in one unit without beingin admixture.

A non-fixed combination or “kit-of-parts” in the present invention isused as known to persons skilled in the art and is defined as acombination wherein the said first active ingredient and the said secondactive ingredient are present in more than one unit. One example of anon-fixed combination or kit-of-parts is a combination wherein the saidfirst active ingredient and the said second active ingredient arepresent separately. The components of the non-fixed combination orkit-of-parts may be administered separately, sequentially,simultaneously, concurrently or chronologically staggered. Any suchcombination of a compound of formula (I) of the present invention withan anti-cancer agent as defined below is an embodiment of the invention.

The term “(chemotherapeutic) anti-cancer agents” relates to any agentthat reduces the survival or proliferation of a cancer cell, andincludes but is not limited to 131I-chTNT, abarelix, abiraterone,aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept,aldesleukin, alemtuzumab, Alendronic acid, alitretinoin, altretamine,amifostine, aminoglutethimide, Hexyl aminolevulinate, amrubicin,amsacrine, anastrozole, ancestim, anethole dithiolethione, angiotensinII, antithrombin III, aprepitant, arcitumomab, arglabin, arsenictrioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan,bendamustine, belinostat, bevacizumab, bexarotene, bicalutamide,bisantrene, bleomycin, bortezomib, buserelin, bosutinib, brentuximabvedotin, busulfan, cabazitaxel, cabozantinib, calcium folinate, calciumlevofolinate, capecitabine, capromab, carboplatin, carfilzomib,carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib,cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir,cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine,copanlisib, crisantaspase, cyclophosphamide, cyproterone, cytarabine,dacarbazine, dactinomycin, darbepoetin alfa, dabrafenib, dasatinib,daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab,depreotide, deslorelin, dexrazoxane, dibrospidium chloride,dianhydrogalactitol, diclofenac, docetaxel, dolasetron, doxifluridine,doxorubicin, doxorubicin+estrone, dronabinol, eculizumab, edrecolomab,elliptinium acetate, eltrombopag, endostatin, enocitabine, enzalutamide,epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta,eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine,etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim,fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide,folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant,gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide,gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine,gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron,granulocyte colony stimulating factor, histamine dihydrochloride,histrelin, hydroxycarbamide, I-125 seeds, lansoprazole, ibandronic acid,ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib,imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate,interferon alfa, interferon beta, interferon gamma, iobitridol,iobenguane (123I), iomeprol, ipilimumab, irinotecan, Itraconazole,ixabepilone, lanreotide, lapatinib, lasocholine, lenalidomide,lenograstim, lentinan, letrozole, leuprorelin, levamisole,levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine,lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol,melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate,methoxsalen, methylaminolevulinate, methylprednisolone,methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin,mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane,mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphinehydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin,naloxone+pentazocine, naltrexone, nartograstim, nedaplatin, nelarabine,neridronic acid, nivolumabpentetreotide, nilotinib, nilutamide,nimorazole, nimotuzumab, nimustine, nitracrine, nivolumab, obinutuzumab,octreotide, ofatumumab, omacetaxine mepesuccinate, omeprazole,ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin,oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel,palifermin, palladium-103 seed, palonosetron, pamidronic acid,panitumumab, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta(methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferonalfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane,perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin,pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate,polyvinylpyrrolidone+sodium hyaluronate, polysaccharide-K, pomalidomide,ponatinib, porfimer sodium, poziotinib, pralatrexate, prednimustine,prednisone, procarbazine, procodazole, propranolol, quinagolide,rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene,raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase,razoxane, refametinib, regorafenib, risedronic acid, rhenium-186etidronate, rituximab, romidepsin, romiplostim, romurtide, roniciclib,samarium (153Sm) lexidronam, sargramostim, satumomab, secretin,sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib,stanozolol, streptozocin, sunitinib, talaporfin, tamibarotene,tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc)nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur,tegafur+gimeracil+oteracil, temoporfin, temozolomide, temsirolimus,teniposide, testosterone, tetrofosmin, thalidomide, thiotepa,thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan,toremifene, tositumomab, trabectedin, tramadol, trastuzumab, trastuzumabemtansine, treosulfan, tretinoin, trifluridine+tipiracil, trilostane,triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan,ubenimex, valatinib, valrubicin, vandetanib, vapreotide, vemurafenib,vinblastine, vincristine, vindesine, vinflunine, vinorelbine,vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres,zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.

By “Epidermal Growth Factor Receptor (EGFR) Polypeptide” is meant apolypeptide having at least about 95% amino acid sequence identity tothe sequence provided at UniProt Accession No. P00533-1 or a fragmentthereof. Mutant EGFR polypeptides include those having an insertionbetween, for example, amino acids V769 and D770 or between D770 andN771. In other embodiments, the amino acid sequence identity is 96, 97,98, 99, or 100% to UniProt Accession No. P00533-1.

An exemplary full length sequence of human EGFR, which indicates V769,D770, and N771 in bold, is provided at UniProt Accession No. P00533-1,which is reproduced below:

(SEQ ID NO: 6) 10 20 30 40 50 MRPSGTAGAA LLALLAALCP ASRALEEKKVCQGTSNKLTQ LGTFEDHFLS 60 70 80 90 100 LQRMFNNCEV VLGNLEITYV QRNYDLSFLKTIQEVAGYVL IALNTVERIP 110 120 130 140 150 LENLQIIRGN MYYENSYALAVLSNYDANKT GLKELPMRNL QEILHGAVRF 160 170 180 190 200 SNNPALCNVESIQWRDIVSS DFLSNMSMDF QNHLGSCQKC DPSCPNGSCW 210 220 230 240 250GAGEENCQKL TKIICAQQCS GRCRGKSPSD CCHNQCAAGC TGPRESDCLV 260 270 280 290300 CRKFRDEATC KDTCPPLMLY NPTTYQMDVN PEGKYSFGAT CVKKCPRNYV 310 320 330340 350 VTDHGSCVRA CGADSYEMEE DGVRKCKKCE GPCRKVCNGI GIGEFKDSLS 360 370380 390 400 INATNIKHFK NCTSISGDLH ILPVAFRGDS FTHTPPLDPQ ELDILKTVKE 410420 430 440 450 ITGFLLIQAW PENRTDLHAF ENLEIIRGRT KQHGQFSLAV VSLNITSLGL460 470 480 490 500 RSLKEISDGD VIISGNKNLC YANTINWKKL FGTSGQKTKIISNRGENSCK 510 520 530 540 550 ATGQVCHALC SPEGCWGPEP RDCVSCRNVSRGRECVDKCN LLEGEPREFV 560 570 580 590 600 ENSECIQCHP ECLPQAMNITCTGRGPDNCI QCAHYIDGPH CVKTCPAGVM 610 620 630 640 650 GENNTLVWKYADAGHVCHLC HPNCTYGCTG PGLEGCPTNG PKIPSIATGM 660 670 680 690 700VGALLLLLVV ALGIGLFMRR RHIVRKRTLR RLLQERELVE PLTPSGEAPN 710 720 730 740750 QALLRILKET EFKKIKVLGS GAFGTVYKGL WIPEGEKVKI PVAIKELREA 760 770 780790 800 TSPKANKEIL DEAYVMASVD NPHVCRLLGI CLTSTVQLIT QLMPFGCLLD 810 820830 840 850 YVREHKDNIG SQYLLNWCVQ IAKGMNYLED RRLVHRDLAA RNVLVKTPQH 860870 880 890 900 VKITDFGLAK LLGAEEKEYH AEGGKVPIKW MALESILHRI YTHQSDVWSY910 920 930 940 950 GVTVWELMTF GSKPYDGIPA SEISSILEKG ERLPQPPICTIDVYMIMVKC 960 970 980 990 1000 WMIDADSRPK FRELIIEFSK MARDPQRYLVIQGDERMHLP SPTDSNFYRA 1010 1020 1030 1040 1050 LMDEEDMDDV VDADEYLIPQQGFFSSPSTS RTPLLSSLSA TSNNSTVACI 1060 1070 1080 1090 1100 DRNGLQSCPIKEDSFLQRYS SDPTGALTED SIDDTFLPVP EYINQSVPKR 1110 1120 1130 1140 1150PAGSVQNPVY HNQPLNPAPS RDPHYQDPHS TAVGNPEYLN TVQPTCVNST 1160 1170 11801190 1200 FDSPAHWAQK GSHQISLDNP DYQQDFFPKE AKPNGIFKGS TAENAEYLRV 1210APQSSEFIGA

An exemplary polynucleotide encoding EGFR is provided at NCBI ReferenceSequence: NM_001346897.1, which is reproduced below:

(SEQ ID NO: 7)   1 gtccgggcag cccccggcgc agcgcggccg cagcagcctc cgccccccgc acggtgtgag  61 cgcccgacgc ggccgaggcg gccggagtcc cgagctagcc ccggcggccg ccgccgccca 121 gaccggacga caggccacct cgtcggcgtc cgcccgagtc cccgcctcgc cgccaacgcc 181 acaaccaccg cgcacggccc cctgactccg tccagtattg atcgggagag ccggagcgag 241 ctcttcgggg agcagcgatg cgaccctccg ggacggccgg ggcagcgctc ctggcgctgc 301 tggctgcgct ctgcccggcg agtcgggctc tggaggaaaa gaaagtttgc caaggcacga 361 gtaacaagct cacgcagttg ggcacttttg aagatcattt tctcagcctc cagaggatgt 421 tcaataactg tgaggtggtc cttgggaatt tggaaattac ctatgtgcag aggaattatg 481 atctttcctt cttaaagacc atccaggagg tggctggtta tgtcctcatt gccctcaaca 541 cagtggagcg aattcctttg gaaaacctgc agatcatcag aggaaatatg tactacgaaa 601 attcctatgc cttagcagtc ttatctaact atgatgcaaa taaaaccgga ctgaaggagc 661 tgcccatgag aaatttacag ggccaaaagt gtgatccaag ctgtcccaat gggagctgct 721 ggggtgcagg agaggagaac tgccagaaac tgaccaaaat catctgtgcc cagcagtgct 781 ccgggcgctg ccgtggcaag tcccccagtg actgctgcca caaccagtgt gctgcaggct 841 gcacaggccc ccgggagagc gactgcctgg tctgccgcaa attccgagac gaagccacgt 901 gcaaggacac ctgcccccca ctcatgctct acaaccccac cacgtaccag atggatgtga 961 accccgaggg caaatacagc tttggtgcca cctgcgtgaa gaagtgtccc cgtaattatg1021 tggtgacaga tcacggctcg tgcgtccgag cctgtggggc cgacagctat gagatggagg1081 aagacggcgt ccgcaagtgt aagaagtgcg aagggccttg ccgcaaagtg tgtaacggaa1141 taggtattgg tgaatttaaa gactcactct ccataaatgc tacgaatatt aaacacttca1201 aaaactgcac ctccatcagt ggcgatctcc acatcctgcc ggtggcattt aggggtgact1261 ccttcacaca tactcctcct ctggatccac aggaactgga tattctgaaa accgtaaagg1321 aaatcacagg gtttttgctg attcaggctt ggcctgaaaa caggacggac ctccatgcct1381 ttgagaacct agaaatcata cgcggcagga ccaagcaaca tggtcagttt tctcttgcag1441 tcgtcagcct gaacataaca tccttgggat tacgctccct caaggagata agtgatggag1501 atgtgataat ttcaggaaac aaaaatttgt gctatgcaaa tacaataaac tggaaaaaac1561 tgtttgggac ctccggtcag aaaaccaaaa ttataagcaa cagaggtgaa aacagctgca1621 aggccacagg ccaggtctgc catgccttgt gctcccccga gggctgctgg ggcccggagc1681 ccagggactg cgtctcttgc cggaatgtca gccgaggcag ggaatgcgtg gacaagtgca1741 accttctgga gggtgagcca agggagtttg tggagaactc tgagtgcata cagtgccacc1801 cagagtgcct gcctcaggcc atgaacatca cctgcacagg acggggacca gacaactgta1861 tccagtgtgc ccactacatt gacggccccc actgcgtcaa gacctgcccg gcaggagtca1921 tgggagaaaa caacaccctg gtctggaagt acgcagacgc cggccatgtg tgccacctgt1981 gccatccaaa ctgcacctac ggatgcactg ggccaggtct tgaaggctgt ccaacgaatg2041 ggcctaagat cccgtccatc gccactggga tggtgggggc cctcctcttg ctgctggtgg2101 tggccctggg gatcggcctc ttcatgcgaa ggcgccacat cgttcggaag cgcacgctgc2161 ggaggctgct gcaggagagg gagcttgtgg agcctcttac acccagtgga gaagctccca2221 accaagctct cttgaggatc ttgaaggaaa ctgaattcaa aaagatcaaa gtgctgggct2281 ccggtgcgtt cggcacggtg tataagggac tctggatccc agaaggtgag aaagttaaaa2341 ttcccgtcgc tatcaaggaa ttaagagaag caacatctcc gaaagccaac aaggaaatcc2401 tcgatgaagc ctacgtgatg gccagcgtgg acaaccccca cgtgtgccgc ctgctgggca2461 tctgcctcac ctccaccgtg cagctcatca cgcagctcat gcccttcggc tgcctcctgg2521 actatgtccg ggaacacaaa gacaatattg gctcccagta cctgctcaac tggtgtgtgc2581 agatcgcaaa gggcatgaac tacttggagg accgtcgctt ggtgcaccgc gacctggcag2641 ccaggaacgt actggtgaaa acaccgcagc atgtcaagat cacagatttt gggctggcca2701 aactgctggg tgcggaagag aaagaatacc atgcagaagg aggcaaagtg cctatcaagt2761 ggatggcatt ggaatcaatt ttacacagaa tctataccca ccagagtgat gtctggagct2821 acggggtgac tgtttgggag ttgatgacct ttggatccaa gccatatgac ggaatccctg2881 ccagcgagat ctcctccatc ctggagaaag gagaacgcct ccctcagcca cccatatgta2941 ccatcgatgt ctacatgatc atggtcaagt gctggatgat agacgcagat agtcgcccaa3001 agttccgtga gttgatcatc gaattctcca aaatggcccg agacccccag cgctaccttg3061 tcattcaggg ggatgaaaga atgcatttgc caagtcctac agactccaac ttctaccgtg3121 ccctgatgga tgaagaagac atggacgacg tggtggatgc cgacgagtac ctcatcccac3181 agcagggctt cttcagcagc ccctccacgt cacggactcc cctcctgagc tctctgagtg3241 caaccagcaa caattccacc gtggcttgca ttgatagaaa tgggctgcaa agctgtccca3301 tcaaggaaga cagcttcttg cagcgataca gctcagaccc cacaggcgcc ttgactgagg3361 acagcataga cgacaccttc ctcccagtgc ctggtgagtg gcttgtctgg aaacagtcct3421 gctcctcaac ctcctcgacc cactcagcag cagccagtct ccagtgtcca agccaggtgc3481 tccctccagc atctccagag ggggaaacag tggcagattt gcagacacag tgaagggcgt3541 aaggagcaga taaacacatg accgagcctg cacaagctct ttgttgtgtc tggttgtttg3601 ctgtacctct gttgtaagaa tgaatctgca aaatttctag cttatgaagc aaatcacgga3661 catacacatc tgtgtgtgtg agtgttcatg atgtgtgtac atctgtgtat gtgtgtgtgt3721 gtatgtgtgt gtttgtgaca gatttgatcc ctgttctctc tgctggctct atcttgacct3781 gtgaaacgta tatttaacta attaaatatt agttaatatt aataaatttt aagctttatc3841 cagaaaaaaa aaaaaaaaa

The intermediates used for the synthesis of the compounds of claims 1-6as described below, as well as their use for the synthesis of thecompounds of claims 1-6, are one further aspect of the presentinvention. Preferred intermediates are the Intermediate Examples asdisclosed below.

General Procedures

The compounds according to the invention can be prepared according tothe following schemes 1-4.

The schemes and procedures described below illustrate synthetic routesto the compounds of general formula (I) of the invention and are notintended to be limiting. It is obvious to the person skilled in the artthat the order of transformations as exemplified in the schemes can bemodified in various ways. The order of transformations exemplified inthe schemes is therefore not intended to be limiting. In addition,interconversion of any of the substituents R¹, R², R³, R⁴, R⁵ and PG canbe achieved before and/or after the exemplified transformations. Thesemodifications can be such as the introduction of protecting groups,cleavage of protecting groups, reduction or oxidation of functionalgroups, halogenation, metallation, substitution or other reactions knownto the person skilled in the art. These transformations include thosewhich introduce a functionality which allows for further interconversionof substituents. Appropriate protecting groups and their introductionand cleavage are well-known to the person skilled in the art. Specificexamples are described in the subsequent paragraphs.

Scheme 1:

Route for the preparation of compounds of general formula (I), whereinR¹, R², R³, R⁴ and R⁵ have the meaning as given for general formula (I)and PG can be hydrogen or optionally a suitable protecting group, e.g.tert-butoxycarbonyl (Boc). In addition, interconversion of any of thesubstituents R¹, R², R³, R⁴, R⁵ and PG can be achieved before and/orafter the exemplified transformations. These modifications can be suchas the introduction of protecting groups, cleavage of protecting groups,reduction or oxidation of functional groups, halogenation, metallation,substitution or other reactions known to the person skilled in the art.These transformations include those which introduce a functionalitywhich allows for further interconversion of substituents. Appropriateprotecting groups and their introduction and cleavage are well-known tothe person skilled in the art. Specific examples are described in thesubsequent paragraphs. Compound of formula 1, 2, and 4 are eithercommercially available or can be prepared according to proceduresavailable from the public domain, as understandable to the personskilled in the art. Specific examples are described in the subsequentparagraphs.

A suitably substituted piperadine-2,4-diones of general formula(Compound of formula 1), such as, for example, 2,4-piperadinedione, canbe reacted with a suitably substituted isothiocyanate (Compound offormula 2), such as, for example, 3-fluorophenylisothiocyanate, in asuitable solvent system, such as, for example, acetonitrile, in thepresence of a suitable base, such as, for example, triethylamine or DBU,at temperatures ranging from −78° C. to +100° C., in some embodimentsthe reaction is carried out at 0° C. or +100° C., to furnish generalformula (3). Similar reactions have been performed in the literature (D.E. Worrall, J. Am. Chem. Soc., 1940, 62, 675).

Intermediates of general formula (3) can be converted to Intermediatesof general formula (5) by reaction with a suitable amine (compounds ofgeneral formula 4), such as, for example 4-(aminomethyl)pyridine, in asuitable solvent system, such as, for example, ethanol and ethylacetate, at a temperature between room temperature and the boiling pointof the respective solvents, in some embodiments the reaction is carriedout at the boiling point of the respective solvents, whereby the waterformed in the reaction is removed from the reaction by methods known tothose skilled in the art, such as, for example, azeotropic removal ofwater (Dean-Stark conditions) or with molecular sieves, to furnishgeneral formula (5).

Intermediates of general formula (3) and intermediates of generalformula (5) in which PG represents a protecting group can be convertedto Intermediates in which PG represents a hydrogen atom using standarddeprotection conditions known to those skilled in the art. When PG is aprotecting group such as, for example, tert-butoxycarbonyl (Boc), thedeprotection can be carried out using acids, such as, for example,hydrochloric acid and trifluoroacetic acid, in a suitable solventsystem, such as, for example, dichloromethane and dioxane, at atemperature between 0° C. and the boiling point of the respectivesolvents, in one embodiment the reaction is carried out at the roomtemperature, to furnish compounds of general formula (3) andintermediates of general formula (5) whereby PG is hydrogen atom.

Intermediates of general formula (5) are reacted with a base and/oroxidizing reagent, in one embodiment an oxidizing agent, such as, forexample hydrogen peroxide or SIBX (stabilized iodoxybenoic acid, in asuitable solvent system, such as, for example, methanol, in atemperature range from −30° C. to the boiling point of the respectivesolvent, in one embodiment the reaction is carried out at the boilingpoint of the respective solvent, to furnish compounds of general formula(I). Optionally, these types of reactions can be carried on with anadditive, such as, for example, an acid or base, such as, for example,acetic acid or trifluoroacetic acid (not-limiting), and triethylamine ordiispropylethylamine (not-limiting).

Intermediates of general formula (5) could be converted to compounds ofgeneral formula (I) by thermal heating them in a suitable solvent atelevated temperatures, which could be above the boiling point of thesaid solvent, such as, for example, RT to +250° C. These reactions couldoptionally be carried out in vessel whereby the pressure can beincreased, such as, for example, in an autoclave. Intermediates ofgeneral formula (5) can also be converted to compounds of generalformula (I) by thermal heating in the presence of a metal catalyst, suchas, for example, palladium on activated charcoal, in a suitable solvent,such as, for example, DMF, DMA, EtOH, MeOH, NMP (not-limiting) atelevated temperatures, such as, for example, RT to +150° C. Optionally,these types of reactions can be carried on with an additive, such as,for example, an acid or base, such as, for example, acetic acid ortrifluoroacetic acid (not-limiting), and triethylamine ordiispropylethylamine (not-limiting), to furnish compounds of generalformula (I).

Scheme 2:

Process for the preparation of compounds of general formula (4), whereinR⁵ has the meaning as given for general formula (I). In addition,interconversion of any of the substituents can be achieved before and/orafter the exemplified transformations. These modifications can be suchas the introduction of protecting groups, cleavage of protecting groups,reduction or oxidation of functional groups, halogenation, metallation,substitution or other reactions known to the person skilled in the art.These transformations include those which introduce a functionalitywhich allows for further interconversion of substituents. Appropriateprotecting groups and their introduction and cleavage are well-known tothe person skilled in the art. Compounds of general formula 6, wherebyLG is a leaving group, such as, for example, F, Cl, Br, I or arylsulfonate such as for example p-toluene sulfonate, or alkyl sulfonatesuch as for example methane sulfonate or trifluoromethane sulfonate, arecommercially available or can be synthesized by those skilled in theart.

Compounds of general formula (6) can be converted to compounds ofgeneral formula (7) by treatment with a suitable nucleophile, such asfor example, amines, alcohols, metal alkoxides, azides, thiols or metalthiolates, under either basic, neutral, acidic, catalytic conditions, inone embodiment basic conditions, in a suitable solvent or using thenucleophile as solvent, such as, for example, DMF, tetrahydrofuran(THF), in a temperature range from −78° C. to the boiling point of therespective solvent, in one embodiment the reaction is carried out −10°C. to the boiling point of the respective solvent, to furnish generalformula (7). Such substitution reactions have been previously reported(Clark et al., J. Med. Chem., 2008, 51, 6631-6634; Guo et al.,Tetrahedron Letts., 2013, 54, 3233-3237; Watterson et al., J. Med.Chem., 2007, 50, 3730-3742; Bellale et al., J. Med. Chem., 2014, 57,6572-6582; Klimesova et al., Eur. J. Med. Chem., 1996, 31, 389-395;Leroy et al., Synth. Commun., 1997, 27, 2905-2916; LaMattina et al., J.Org. Chem., 1981, 46, 4179-4182; Beugelmans et al., Tetrahedron, 1983,39, 4153-4162).

Compounds of general formula (7) can be converted to compounds ofgeneral formula (4) by many reducing methods known to those skilled inthe art, using numerous different reagents and reaction conditions; suchmethods and reagents can be carried out with metal hydrides, such as,for example, lithium aluminum hydride in THF (Bullock et al., J. Am.Chem. Soc., 1956, 78, 490, Wang et al., J. Org. Chem., 2006, 71,4021-3160), or using zinc in acetic acid (Rabe, Chem. Ber., 1913, 46,1024), or using diborane (De Munno et al., Heterocycles, 1996, 43,1893-1900), or using catalytic hydrogenation methods, for example,hydrogen and palladium on carbon under acidic conditions (Stokker etal., J. Med. Chem., 1981, 24, 115-117; Bertini et al., J. Med. Chem.,2005, 48, 664-670), hydrogen and nickel under basic conditions (Walpoleet al., J. Med. Chem., 1993, 36, 2362-2372, Kuramochi et al., Bioorg.Med. Chem., 2005, 13, 4022-4036.)

Scheme 3:

Process for the preparation of compounds of general formula 2, whereinR^(1a) represents methyl or difluoromethyl corresponding to R¹ in thegeneral formula (I) with the meaning of methoxy and difluoromethoxy. Thesynthesis of compounds 9 and 10 relates to alkoxy substitution of thephenyl ring. However, the isothiocyanate containing product 2 and thesynthesis thereof (i.e., 10→2 or 11→2) is general to R¹ groups accordingto general formula (I). In addition, interconversion of any of thesubstituents can be achieved before and/or after the exemplifiedtransformations. These modifications can be such as the introduction ofprotecting groups, cleavage of protecting groups, reduction or oxidationof functional groups, halogenation, metallation, substitution or otherreactions known to the person skilled in the art. These transformationsinclude those which introduce a functionality which allows for furtherinterconversion of substituents. Appropriate protecting groups and theirintroduction and cleavage are well-known to the person skilled in theart.

Compounds of general formula (8), can be converted to compounds ofgeneral formula (9), using various methods which are known to thoseskilled in the art. Such transformations could be, for example, toalkylate the phenolic alcohol with alkylating reagents, such as, forexample, alkyl halides, alkyl sulfonates, in which these alkyl groupscan optionally contain fluorides, alkoxyl groups. These alkylationreactions are known to those skilled in the art using a variety ofmethods: i) K₂CO₃ in a solvent such as, DMF, acetone, DMFA (see theteachings of Muro et al., J. Med. Chem., 2009, 52, 7974 and WO2009/20990A1); ii) KOH in EtOH (see the teachings of Macias et al., J. Agric. FoodChem., 2006, 54, 9843); iii) Mitsunobu reaction (see the teachings ofUS2006/122168 A1 and EP2151431 A1) to furnish intermediates of generalformula (9).

Compounds of general formula (9) can be converted to compounds ofgeneral formula (10) by reduction methods and these methods are known tothose skilled in the art. These reductions can be carried using: i)hydrogen gas and a catalyst (for Pd/C as catalyst see the teachings ofChan et al., J. Am. Chem. Soc., 2011, 133, 2989; for platinum see theteachings of Niemann et al., J. Am. Chem Soc., 1941, 63, 2204; forRaney-Nickel see the teachings of US2009/253767 A1); ii) iron andammonium chloride (see the teachings of Sweeney et al., Bioorg. Med.Chem. Lett., 2008, 18, 4348); iii) sodium dithionite (see the teachingsof Chong et al., J. Med. Chem., 2012, 55, 10601); iv) zinc and ammoniumchloride (see the teachings of WO2010/42699 A1) to furnish intermediatesof general formula (10).

Compounds of general formula (10) can be converted to compounds ofgeneral formula (2) by using reagents such as, for example,thiophosgene, carbon disulphide, 1,1″-thiocarbonyldi-2(1H)-pyridone or1,1′-thiocarbonyldiimidazole, in one embodiment thiophosgene, underbasic conditions, in a suitable solvent, such as, for example,dichloromethane, chloroform, acetone, or biphasic mixtures, such as, forexample, dichloromethane, chloroform with aqueous basic solutions, inanother embodiment, dichloromethane with an aqueous saturated solutionof sodium hydrogen carbonate or sodium carbonate, in a temperature rangefrom −78° C. to the boiling point of the respective solvent, in anotherembodiment the reaction is carried out 0° C. to room temperature, tofurnish compounds of general formula (2). Such transformations reactionshave been previously reported (Harris et al., J. Med. Chem., 2005, 48,1610; Degorce et al., Tetrahedron Lett., 2011, 52, 6719; WO2016/91845A1; Fairhurst et al., Org. Lett., 2005, 7, 4697; Chaskar et al., Synth.Commun., 2008, 38, 16940; US2004/122237 A1).

Scheme 4:

Route for the preparation of compounds of general formula (I), whereinR¹, R², R³, R⁴ and R⁵ have the meaning as given for general formula (I)and PG can be hydrogen or optionally a suitable protecting group, e.g.tert-butoxycarbonyl (Boc). In addition, interconversion of any of thesubstituents R¹, R², R³, R⁴, R⁵ and PG can be achieved before and/orafter the exemplified transformations. These modifications can be suchas the introduction of protecting groups, cleavage of protecting groups,reduction or oxidation of functional groups, halogenation, metallation,substitution or other reactions known to the person skilled in the art.These transformations include those which introduce a functionalitywhich allows for further interconversion of substituents. Appropriateprotecting groups and their introduction and cleavage are well-known tothe person skilled in the art. Specific examples are described in thesubsequent paragraphs.

Compounds similar to those of general formula 12 are known to thoseskilled in the art and their syntheses have been reported in theliterature (see the teachings of Voss et al., WO2015/22073 A1; Hart etal., WO2016/100166 A1; Anderson et al., J. Med. Chem., 2007, 50, 2647;Vanotti et al., J. Med. Chem., 2008, 51, 487).

Compounds of general formula (12) could be converted to compounds ofgeneral formula (13) using standard bromination methods which are knownto those skilled in the art (WO2016/100166 A1). Such brominations couldbe carried out using a brominating agent, such as, for example,N-bromosuccinimide, in a suitable solvent, such as, for example, DMF, ina temperature range from −78° C. to the boiling point of said solvent,in one embodiment the temperature range is 0° C. to RT.

Intermediates of general formula (13) can be reacted with suitableanilines, such as, for example, 2-difluoromethoxyaniline, in thepresence of a base, such as, for example, lithiumbis(trimethylsilyl)amide (LHMDS), in the presence of a catalyst, suchas, for example a suitable ligand, in one embodiment2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl(tBuBrettPhos) and in the presence of a pre-catalyst, such as, forexample a palladium pre-catalyst, in another embodimentchloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II)(BrettPhos-PreCat MTBE ether adduct) in a suitable solvent system, suchas, for example, tetrahydrofuran (THF), at a temperature range of 0° C.to 200° C. In one embodiment, the reaction is carried out at 80° C., tofurnish compounds of general formula (I). Similar transformations havebeen carried out and have been reported (WO2015/193339 A1).

It is known to the person skilled in the art that, if there are a numberof reactive centers on a starting or intermediate compound, it may benecessary to block one or more reactive centers temporarily byprotective groups in order to allow a reaction to proceed specificallyat the desired reaction center.

The compounds according to the invention are isolated and purified in amanner known per se, e.g. by distilling off the solvent in vacuo andrecrystallizing the residue obtained from a suitable solvent orsubjecting it to one of the customary purification methods, such aschromatography on a suitable support material. Furthermore, reversephase preparative HPLC may be applied. The compounds of the presentinvention which possess a sufficiently basic or acidic functionality,may result as a salt, such as, in the case of a compound of the presentinvention which is sufficiently basic, a trifluoroacetate or formatesalt for example, or, in the case of a compound of the present inventionwhich is sufficiently acidic, an ammonium salt for example. Salts ofthis type can either be transformed into its free base or free acidform, respectively, by various methods known to the person skilled inthe art, or be used as salts in subsequent biological assays.Additionally, the drying process during the isolation of the compoundsof the present invention may not fully remove traces of cosolvents,especially such as formic acid or trifluoroacetic acid, to give solvatesor inclusion complexes. The person skilled in the art will recognisewhich solvates or inclusion complexes are acceptable to be used insubsequent biological assays. It is to be understood that the specificform (e.g. salt, free base, free acid, solvate, inclusion complex) of acompound of the present invention as isolated and described herein isnot necessarily the only form in which said compound can be applied to abiological assay in order to quantify the specific biological activity.

Salts of the compounds of formula (I) according to the invention can beobtained by dissolving the free compound in a suitable solvent (forexample a ketone such as acetone, methylethylketone ormethylisobutylketone, an ether such as diethyl ether, tetrahydrofuran ordioxane, a chlorinated hydrocarbon such as methylene chloride orchloroform, or a low molecular weight aliphatic alcohol such asmethanol, ethanol or isopropanol) which contains the desired acid orbase, or to which the desired acid or base is then added. The acid orbase can be employed in salt preparation, depending on whether a mono-or polybasic acid or base is concerned and depending on which salt isdesired, in an equimolar ratio or one differing therefrom. The salts areobtained by filtering, reprecipitating, precipitating with a non-solventfor the salt or by evaporating the solvent. Salts obtained can beconverted into the free compounds which, in turn, can be converted intosalts. In this manner, pharmaceutically unacceptable salts, which can beobtained, for example, as process products in the manufacturing on anindustrial scale, can be converted into pharmaceutically acceptablesalts by processes known to the person skilled in the art. Especiallypreferred are hydrochlorides and the process used in the examplesection.

Pure diastereomers and pure enantiomers of the compounds and saltsaccording to the invention can be obtained e.g. by asymmetric synthesis,by using chiral starting compounds in synthesis or by splitting upenantiomeric and diasteriomeric mixtures obtained in synthesis.

Enantiomeric and diastereomeric mixtures can be split up into the pureenantiomers and pure diastereomers by methods known to the personskilled in the art. In one embodiment, diastereomeric mixtures areseparated by crystallization, in particular fractional crystallization,or chromatography. Enantiomeric mixtures can be separated e.g. byforming diastereomers with a chiral auxiliary agent, resolving thediastereomers obtained and removing the chiral auxiliary agent. Aschiral auxiliary agents, for example, chiral acids can be used toseparate enantiomeric bases such as e.g. mandelic acid and chiral basescan be used to separate enantiomeric acids by formation ofdiastereomeric salts. Furthermore, diastereomeric derivatives such asdiastereomeric esters can be formed from enantiomeric mixtures ofalcohols or enantiomeric mixtures of acids, respectively, using chiralacids or chiral alcohols, respectively, as chiral auxiliary agents.Additionally, diastereomeric complexes or diastereomeric clathrates maybe used for separating enantiomeric mixtures. Alternatively,enantiomeric mixtures can be split up using chiral separating columns inchromatography. Another suitable method for the isolation of enantiomersis the enzymatic separation.

One preferred aspect of the invention is the process for the preparationof the compounds of claims 1-4 according to the examples as well as theintermediates used for their preparation.

Optionally, compounds of the formula (I) can be converted into theirsalts, or, optionally, salts of the compounds of the formula (I) can beconverted into the free compounds. Corresponding processes are customaryfor the skilled person.

Commercial Utility

As mentioned supra, the compounds of the present invention havesurprisingly been found to effectively inhibit mutant EGFR finallyresulting in cell death (e.g., apoptosis) and may therefore be used forthe treatment or prophylaxis of diseases of uncontrolled cell growth,proliferation and/or survival, inappropriate cellular immune responses,or inappropriate cellular inflammatory responses, or diseases which areaccompanied with uncontrolled cell growth, proliferation and/orsurvival, inappropriate cellular immune responses, or inappropriatecellular inflammatory responses, particularly in which the uncontrolledcell growth, proliferation and/or survival, inappropriate cellularimmune responses, or inappropriate cellular inflammatory responses ismediated by mutant EGFR, such as, for example, benign and malignantneoplasia, more specifically haematological tumours, solid tumours,and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome,malignant lymphomas, head and neck tumours including brain tumours andbrain metastases, tumours of the thorax including non-small cell andsmall cell lung tumours, gastrointestinal tumours, endocrine tumours,mammary and other gynaecological tumours, urological tumours includingrenal, bladder and prostate tumours, skin tumours, and sarcomas, and/ormetastases thereof, especially haematological tumours, solid tumours,and/or metastases of breast, bladder, bone, brain, central andperipheral nervous system, cervix, colon, endocrine glands (e.g.,thyroid and adrenal cortex), endocrine tumours, endometrium, esophagus,gastrointestinal tumours, germ cells, kidney, liver, lung, larynx andhypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, renal,small intestine, soft tissue, stomach, skin, testis, ureter, vagina andvulva as well as malignant neoplasias including primary tumours in saidorgans and corresponding secondary tumours in distant organs (“tumourmetastases”). Haematological tumours can e.g be exemplified byaggressive and indolent forms of leukemia and lymphoma, namelynon-Hodgkins disease, chronic and acute myeloid leukemia (CML/AML),acute lymphoblastic leukemia (ALL), Hodgkins disease, multiple myelomaand T-cell lymphoma. Also included are myelodysplastic syndrome, plasmacell neoplasia, paraneoplastic syndromes, and cancers of unknown primarysite as well as AIDS related malignancies.

A further aspect of the invention is the use of the compounds accordingto formula (I) for the treatment of lung cancer, particularly lungcancer harboring mutant EGFR with exon insertion mutations, moreparticularly lung cancer harboring V769_770ins ASV and/or D770_N771insSVD exon 20 insertions, and/or metastases thereof, comprisingadministering an effective amount of a compound of formula (I).

In accordance with an aspect of the present invention therefore theinvention relates to a compound of general formula I, or an N-oxide, asalt, a tautomer or a stereoisomer of said compound, or a salt of saidN-oxide, tautomer or stereoisomer particularly a pharmaceuticallyacceptable salt thereof, or a mixture of same, as described and definedherein, for use in the treatment or prophylaxis of a disease, especiallyfor use in the treatment of a disease.

Another particular aspect of the present invention is therefore the useof a compound of general formula I, described supra, or a stereoisomer,a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof,particularly a pharmaceutically acceptable salt thereof, or a mixture ofsame, for the prophylaxis or treatment of hyperproliferative disordersor disorders responsive to induction of cell death i.e apoptosis.

The term “inappropriate” within the context of the present invention, inparticular in the context of “inappropriate cellular immune responses,or inappropriate cellular inflammatory responses”, as used herein, is tobe understood as generally meaning a response which is less than, orgreater than normal, and which is associated with, responsible for, orresults in, the pathology of said diseases.

In particular embodiments, the use is in the treatment or prophylaxis ofdiseases, especially the treatment, wherein the diseases arehaematological tumours, solid tumours and/or metastases thereof.

Another aspect is the use of a compound of formula (I) for theprophylaxis and/or treatment of lung cancer, particularly lung cancerharboring mutant EGFR with exon 20 insertion mutations, moreparticularly lung cancer harboring V769_770ins ASV and/or D770_N771insSVD exon 20 insertions, and/or metastases thereof, especially preferredfor the treatment thereof.

Another aspect of the present invention is the use of a compound offormula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, asolvate, or a salt thereof, particularly a pharmaceutically acceptablesalt thereof, or a mixture of same, as described herein, in themanufacture of a medicament for the treatment or prophylaxis of adisease, wherein such disease is a hyperproliferative disorder or adisorder responsive to induction of cell death e.g., apoptosis. In anembodiment the disease is a haematological tumour, a solid tumour and/ormetastases thereof. In another embodiment the disease is lung cancer,particularly lung cancer harboring mutant EGFR with exon 20 insertionmutations, more particularly lung cancer harboring V769_770ins ASVand/or D770_N771ins SVD exon 20 insertions, and/or metastases thereof.

Method of Treating Hyper-Proliferative Disorders

The present invention relates to a method for using the compounds of thepresent invention and compositions thereof, to treat mammalianhyper-proliferative disorders. Compounds can be utilized to inhibit,block, reduce, decrease, etc., cell proliferation and/or cell division,and/or produce cell death e.g. apoptosis. This method comprisesadministering to a mammal in need thereof, including a human, an amountof a compound of this invention, or a pharmaceutically acceptable salt,isomer, polymorph, metabolite, hydrate, solvate or ester thereof; etc.which is effective to treat the disorder. Hyper-proliferative disordersinclude but are not limited, e.g., psoriasis, keloids, and otherhyperplasias affecting the skin, benign prostate hyperplasia (BPH),solid tumours, such as cancers of the breast, respiratory tract, brain,reproductive organs, digestive tract, urinary tract, eye, liver, skin,head and neck, thyroid, parathyroid and their distant metastases. Thosedisorders also include lymphomas, sarcomas, and leukaemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem andhypothalmic glioma, cerebellar and cerebral astrocytoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumour.

Tumours of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumours of the female reproductiveorgans include, but are not limited to endometrial, cervical, ovarian,vaginal, and vulvar cancer, as well as sarcoma of the uterus.

Tumours of the digestive tract include, but are not limited to anal,colon, colorectal, oesophageal, gallbladder, gastric, pancreatic,rectal, small-intestine, and salivary gland cancers.

Tumours of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, urethral and human papillary renalcancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixedhepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, inverted sinonasal papilloma,inverted sinonasal papilloma-associated sinonasal squamous cellcarcinoma, Merkel cell skin cancer, and non-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to laryngeal,hypopharyngeal, nasopharyngeal, oropharyngeal cancer, inverted sinonasalpapilloma, inverted sinonasal papilloma-associated sinonasal squamouscell carcinoma, lip and oral cavity cancer and squamous cell. Lymphomasinclude, but are not limited to AIDS-related lymphoma, non-Hodgkin'slymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin'sdisease, and lymphoma of the central nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

These disorders have been well characterized in humans, but also existwith a similar etiology in other mammals, and can be treated byadministering pharmaceutical compositions of the present invention.

The term “treating” or “treatment” as stated throughout this document isused conventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of, etc., of a disease or disorder, such as a carcinoma.

Methods of Treating Kinase Disorders

The present invention also provides methods for the treatment ofdisorders associated with aberrant mitogen extracellular kinaseactivity, including, but not limited to stroke, heart failure,hepatomegaly, cardiomegaly, diabetes, Alzheimer's disease, cysticfibrosis, symptoms of xenograft rejections, septic shock or asthma.

Effective amounts of compounds of the present invention can be used totreat such disorders, including those diseases (e.g., cancer) mentionedin the Background section above. Nonetheless, such cancers and otherdiseases can be treated with compounds of the present invention,regardless of the mechanism of action and/or the relationship betweenthe kinase and the disorder.

The phrase “aberrant kinase activity” or “aberrant tyrosine kinaseactivity,” includes any abnormal expression or activity of the geneencoding the kinase or of the polypeptide it encodes. Examples of suchaberrant activity, include, but are not limited to, overexpression ofthe gene or polypeptide; gene amplification; mutations which produceconstitutively-active or hyperactive kinase activity; gene mutations,deletions, substitutions, additions, etc.

The present invention also provides for methods of inhibiting kinaseactivity, especially of mitogen extracellular kinase, comprisingadministering an effective amount of a compound of the presentinvention, including salts, polymorphs, metabolites, hydrates, solvates,prodrugs (e.g.: esters) thereof, and diastereoisomeric forms thereof.Kinase activity can be inhibited in cells (e.g., in vitro), or in thecells of a mammalian subject, especially a human patient in need oftreatment.

Methods of Treating Angiogenic Disorders

The present invention also provides methods of treating disorders anddiseases associated with excessive and/or abnormal angiogenesis.

Inappropriate and ectopic expression of angiogenesis can be deleteriousto an organism. A number of pathological conditions are associated withthe growth of extraneous blood vessels. These include, e.g., diabeticretinopathy, ischemic retinal-vein occlusion, and retinopathy ofprematurity [Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer etal. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD;see, Lopez et al. Invest. Ophthalmol. Vis. Sci. 1996, 37, 855],neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma,inflammation, rheumatoid arthritis (RA), restenosis, in-stentrestenosis, vascular graft restenosis, etc. In addition, the increasedblood supply associated with cancerous and neoplastic tissue, encouragesgrowth, leading to rapid tumour enlargement and metastasis. Moreover,the growth of new blood and lymph vessels in a tumour provides an escaperoute for renegade cells, encouraging metastasis and the consequencespread of the cancer. Thus, compounds of the present invention can beutilized to treat and/or prevent any of the aforementioned angiogenesisdisorders, e.g., by inhibiting and/or reducing blood vessel formation;by inhibiting, blocking, reducing, decreasing, etc. endothelial cellproliferation or other types involved in angiogenesis, as well ascausing cell death e.g. apoptosis of such cell types.

In various embodiments, the diseases of said method are haematologicaltumours, solid tumour and/or metastases thereof.

The compounds of the present invention can be used in particular intherapy and prevention i.e. prophylaxis, especially in therapy of tumourgrowth and metastases, especially in solid tumours of all indicationsand stages with or without pre-treatment of the tumour growth.

Pharmaceutical Compositions of the Compounds of the Invention

This invention also relates to pharmaceutical compositions containingone or more compounds of the present invention. These compositions canbe utilised to achieve the desired pharmacological effect byadministration to a patient in need thereof. A patient, for the purposeof this invention, is a mammal, including a human, in need of treatmentfor the particular condition or disease.

Therefore, the present invention includes pharmaceutical compositionsthat are comprised of a pharmaceutically acceptable carrier or auxiliaryand a pharmaceutically effective amount of a compound, or salt thereof,of the present invention.

Another aspect of the invention is a pharmaceutical compositioncomprising a pharmaceutically effective amount of a compound of formula(I) and a pharmaceutically acceptable auxiliary for the treatment of adisease mentioned supra, especially for the treatment of haematologicaltumours, solid tumours and/or metastases thereof.

A pharmaceutically acceptable carrier or auxiliary is preferably acarrier that is non-toxic and innocuous to a patient at concentrationsconsistent with effective activity of the active ingredient so that anyside effects ascribable to the carrier do not vitiate the beneficialeffects of the active ingredient. Carriers and auxiliaries are all kindsof additives assisting to the composition to be suitable foradministration.

A pharmaceutically effective amount of compound is preferably thatamount which produces a result or exerts the intended influence on theparticular condition being treated.

The compounds of the present invention can be administered withpharmaceutically-acceptable carriers or auxiliaries well known in theart using any effective conventional dosage unit forms, includingimmediate, slow and timed release preparations, orally, parenterally,topically, nasally, ophthalmically, optically, sublingually, rectally,vaginally, and the like.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, lozenges,melts, powders, solutions, suspensions, or emulsions, and may beprepared according to methods known to the art for the manufacture ofpharmaceutical compositions. The solid unit dosage forms can be acapsule that can be of the ordinary hard- or soft-shelled gelatine typecontaining auxiliaries, for example, surfactants, lubricants, and inertfillers such as lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tabletedwith conventional tablet bases such as lactose, sucrose and cornstarchin combination with binders such as acacia, corn starch or gelatine,disintegrating agents intended to assist the break-up and dissolution ofthe tablet following administration such as potato starch, alginic acid,corn starch, and guar gum, gum tragacanth, acacia, lubricants intendedto improve the flow of tablet granulation and to prevent the adhesion oftablet material to the surfaces of the tablet dies and punches, forexample talc, stearic acid, or magnesium, calcium or zinc stearate,dyes, colouring agents, and flavouring agents such as peppermint, oil ofwintergreen, or cherry flavouring, intended to enhance the aestheticqualities of the tablets and make them more acceptable to the patient.Suitable excipients for use in oral liquid dosage forms includedicalcium phosphate and diluents such as water and alcohols, forexample, ethanol, benzyl alcohol, and polyethylene alcohols, either withor without the addition of a pharmaceutically acceptable surfactant,suspending agent or emulsifying agent. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance tablets, pills or capsules may be coated withshellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of anaqueous suspension. They provide the active ingredient in admixture witha dispersing or wetting agent, a suspending agent and one or morepreservatives. Suitable dispersing or wetting agents and suspendingagents are exemplified by those already mentioned above. Additionalexcipients, for example those sweetening, flavouring and colouringagents described above, may also be present.

The pharmaceutical compositions of this invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oilsuch as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived form fattyacids and hexitol anhydrides, for example, sorbitan monooleate, (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavouring agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as, for example, arachis oil, olive oil, sesameoil or coconut oil, or in a mineral oil such as liquid paraffin. Theoily suspensions may contain a thickening agent such as, for example,beeswax, hard paraffin, or cetyl alcohol. The suspensions may alsocontain one or more preservatives, for example, ethyl or n-propylp-hydroxybenzoate; one or more colouring agents; one or more flavouringagents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, and preservative, such asmethyl and propyl parabens and flavouring and colouring agents.

The compounds of this invention may also be administered parenterally,that is, subcutaneously, intravenously, intraocularly, intrasynovially,intramuscularly, or interperitoneally, as injectable dosages of thecompound in preferably a physiologically acceptable diluent with apharmaceutical carrier which can be a sterile liquid or mixture ofliquids such as water, saline, aqueous dextrose and related sugarsolutions, an alcohol such as ethanol, isopropanol, or hexadecylalcohol, glycols such as propylene glycol or polyethylene glycol,glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, etherssuch as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acidester or, a fatty acid glyceride, or an acetylated fatty acid glyceride,with or without the addition of a pharmaceutically acceptable surfactantsuch as a soap or a detergent, suspending agent such as pectin,carbomers, methylcellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agent and other pharmaceuticaladjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum and mineral oil. Suitable fattyacids include oleic acid, stearic acid, isostearic acid and myristicacid. Suitable fatty acid esters are, for example, ethyl oleate andisopropyl myristate. Suitable soaps include fatty acid alkali metal,ammonium, and triethanolamine salts and suitable detergents includecationic detergents, for example dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergents,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents,for example, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxidecopolymers; and amphoteric detergents, for example,alkyl-beta-aminopropionates, and 2-alkylimidazoline quaternary ammoniumsalts, as well as mixtures.

The parenteral compositions of this invention will typically containfrom about 0.5% to about 25% by weight of the active ingredient insolution. Preservatives and buffers may also be used advantageously. Inorder to minimise or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) in one embodiment of from about 12 toabout 17. The quantity of surfactant in such formulation in oneembodiment ranges from about 5% to about 15% by weight. The surfactantcan be a single component having the above HLB or can be a mixture oftwo or more components having the desired HLB.

Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The pharmaceutical compositions may be in the form of sterile injectableaqueous suspensions. Such suspensions may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents such as, for example, sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents which may be a naturally occurring phosphatide such aslecithin, a condensation product of an alkylene oxide with a fatty acid,for example, polyoxyethylene stearate, a condensation product ofethylene oxide with a long chain aliphatic alcohol, for example,heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxidewith a partial ester derived form a fatty acid and a hexitol such aspolyoxyethylene sorbitol monooleate, or a condensation product of anethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent. Diluents and solvents that may be employed are, for example,water, Ringer's solution, isotonic sodium chloride solutions andisotonic glucose solutions. In addition, sterile fixed oils areconventionally employed as solvents or suspending media. For thispurpose, any bland, fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be usedin the preparation of injectables.

A composition of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritationexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are, for example, cocoa butter and polyethyleneglycol.

Controlled release formulations for parenteral administration includeliposomal, polymeric microsphere and polymeric gel formulations that areknown in the art.

It may be desirable or necessary to introduce the pharmaceuticalcomposition to the patient via a mechanical delivery device. Theconstruction and use of mechanical delivery devices for the delivery ofpharmaceutical agents is well known in the art. Direct techniques foradministration, for example, administering a drug directly to the brainusually involve placement of a drug delivery catheter into the patient'sventricular system to bypass the blood-brain barrier. One suchimplantable delivery system, used for the transport of agents tospecific anatomical regions of the body, is described in U.S. Pat. No.5,011,472, issued Apr. 30, 1991.

The compositions of the invention can also contain other conventionalpharmaceutically acceptable compounding ingredients, generally referredto as carriers or diluents, as necessary or desired. Conventionalprocedures for preparing such compositions in appropriate dosage formscan be utilized.

Such ingredients and procedures include those described in the followingreferences, each of which is incorporated herein by reference: Powell,M. F. et al., “Compendium of Excipients for Parenteral Formulations” PDAJournal of Pharmaceutical Science & Technology 1998, 52(5), 238-311;Strickley, R. G “Parenteral Formulations of Small Molecule TherapeuticsMarketed in the United States (1999)-Part-1” PDA Journal ofPharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S.et al., “Excipients and Their Use in Injectable Products” PDA Journal ofPharmaceutical Science & Technology 1997, 51(4), 166-171.

Commonly used pharmaceutical ingredients that can be used as appropriateto formulate the composition for its intended route of administrationinclude:

acidifying agents (examples include but are not limited to acetic acid,citric acid, fumaric acid, hydrochloric acid, nitric acid);

alkalinizing agents (examples include but are not limited to ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide,triethanolamine, trolamine);

adsorbents (examples include but are not limited to powdered celluloseand activated charcoal);

aerosol propellants (examples include but are not limited to carbondioxide, CCl₂F₂, F₂ClC—CClF₂ and CClF₃);

air displacement agents (examples include but are not limited tonitrogen and argon); antifungal preservatives (examples include but arenot limited to benzoic acid, butylparaben, ethylparaben, methylparaben,propylparaben, sodium benzoate);

antimicrobial preservatives (examples include but are not limited tobenzalkonium chloride, benzethonium chloride, benzyl alcohol,cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol,phenylmercuric nitrate and thimerosal);

antioxidants (examples include but are not limited to ascorbic acid,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate,sodium bisulfite, sodium formaldehyde sulfoxylate, sodiummetabisulfite);binding materials (examples include but are not limited to blockpolymers, natural and synthetic rubber, polyacrylates, polyurethanes,silicones, polysiloxanes and styrene-butadiene copolymers);buffering agents (examples include but are not limited to potassiummetaphosphate, dipotassium phosphate, sodium acetate, sodium citrateanhydrous and sodium citrate di hydrate);carrying agents (examples include but are not limited to acacia syrup,aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orangesyrup, syrup, corn oil, mineral oil, peanut oil, sesame oil,bacteriostatic sodium chloride injection and bacteriostatic water forinjection);chelating agents (examples include but are not limited to edetatedisodium and edetic acid);colourants (examples include but are not limited to FD&C Red No. 3, FD&CRed No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&COrange No. 5, D&C Red No. 8, caramel and ferric oxide red);clarifying agents (examples include but are not limited to bentonite);emulsifying agents (examples include but are not limited to acacia,cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitanmonooleate, polyoxyethylene 50 monostearate);encapsulating agents (examples include but are not limited to gelatinand cellulose acetate phthalate);flavourants (examples include but are not limited to anise oil, cinnamonoil, cocoa, menthol, orange oil, peppermint oil and vanillin);humectants (examples include but are not limited to glycerol, propyleneglycol and sorbitol);levigating agents (examples include but are not limited to mineral oiland glycerin); oils (examples include but are not limited to arachisoil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil);ointment bases (examples include but are not limited to lanolin,hydrophilic ointment, polyethylene glycol ointment, petrolatum,hydrophilic petrolatum, white ointment, yellow ointment, and rose waterointment);penetration enhancers (transdermal delivery) (examples include but arenot limited to monohydroxy or polyhydroxy alcohols, mono- or polyvalentalcohols, saturated or unsaturated fatty alcohols, saturated orunsaturated fatty esters, saturated or unsaturated dicarboxylic acids,essential oils, phosphatidyl derivatives, cephalin, terpenes, amides,ethers, ketones and ureas);plasticizers (examples include but are not limited to diethyl phthalateand glycerol);solvents (examples include but are not limited to ethanol, corn oil,cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanutoil, purified water, water for injection, sterile water for injectionand sterile water for irrigation);stiffening agents (examples include but are not limited to cetylalcohol, cetyl esters wax, microcrystalline wax, paraffin, stearylalcohol, white wax and yellow wax);suppository bases (examples include but are not limited to cocoa butterand polyethylene glycols (mixtures));surfactants (examples include but are not limited to benzalkoniumchloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium laurylsulfate and sorbitan mono-palmitate);suspending agents (examples include but are not limited to agar,bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,kaolin, methylcellulose, tragacanth and veegum);sweetening agents (examples include but are not limited to aspartame,dextrose, glycerol, mannitol, propylene glycol, saccharin sodium,sorbitol and sucrose);tablet anti-adherents (examples include but are not limited to magnesiumstearate and talc);tablet binders (examples include but are not limited to acacia, alginicacid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose,gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);tablet and capsule diluents (examples include but are not limited todibasic calcium phosphate, kaolin, lactose, mannitol, microcrystallinecellulose, powdered cellulose, precipitated calcium carbonate, sodiumcarbonate, sodium phosphate, sorbitol and starch);tablet coating agents (examples include but are not limited to liquidglucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetatephthalate and shellac);tablet direct compression excipients (examples include but are notlimited to dibasic calcium phosphate);tablet disintegrants (examples include but are not limited to alginicacid, carboxymethylcellulose calcium, microcrystalline cellulose,polacrillin potassium, crosslinked polyvinylpyrrolidone, sodiumalginate, sodium starch glycollate and starch);tablet qlidants (examples include but are not limited to colloidalsilica, corn starch and talc);tablet lubricants (examples include but are not limited to calciumstearate, magnesium stearate, mineral oil, stearic acid and zincstearate);tablet/capsule opaquants (examples include but are not limited totitanium dioxide); tablet polishing agents (examples include but are notlimited to carnuba wax and white wax);thickening agents (examples include but are not limited to beeswax,cetyl alcohol and paraffin);tonicity agents (examples include but are not limited to dextrose andsodium chloride);viscosity increasing agents (examples include but are not limited toalginic acid, bentonite, carbomers, carboxymethylcellulose sodium,methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth);andwetting agents (examples include but are not limited toheptadecaethylene oxycetanol, lecithins, sorbitol monooleate,polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

Pharmaceutical compositions according to the present invention can beillustrated as follows:

Sterile i.v. Solution:

A 5 mg/ml solution of the desired compound of this invention can be madeusing sterile, injectable water, and the pH is adjusted if necessary.The solution is diluted for administration to 1-2 mg/ml with sterile 5%dextrose and is administered as an i.v. infusion over about 60 minutes.

Lyophilised Powder for i.v. Administration:

A sterile preparation can be prepared with (i) 100-1000 mg of thedesired compound of this invention as a lyophilised powder, (ii) 32-327mg/ml sodium citrate, and (iii) 300-3000 mg Dextran 40. The formulationis reconstituted with sterile, injectable saline or dextrose 5% to aconcentration of 10 to 20 mg/ml, which is further diluted with saline ordextrose 5% to 0.2-0.4 mg/ml, and is administered either IV bolus or byIV infusion over 15-60 minutes.

Intramuscular Suspension:

The following solution or suspension can be prepared, for intramuscularinjection:

50 mg/ml of the desired, water-insoluble compound of this invention

5 mg/ml sodium carboxymethylcellulose

4 mg/ml TWEEN 80

9 mg/ml sodium chloride

9 mg/ml benzyl alcohol

Hard Shell Capsules:

A large number of unit capsules are prepared by filling standardtwo-piece hard galantine capsules each with 100 mg of powdered activeingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesiumstearate.

Soft Gelatin Capsules:

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil is prepared and injected by means of apositive displacement pump into molten gelatin to form soft gelatincapsules containing 100 mg of the active ingredient. The capsules arewashed and dried. The active ingredient can be dissolved in a mixture ofpolyethylene glycol, glycerin and sorbitol to prepare a water misciblemedicine mix.

Tablets:

A large number of tablets are prepared by conventional procedures sothat the dosage unit is 100 mg of active ingredient, 0.2 mg. ofcolloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg ofmicrocrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose.Appropriate aqueous and non-aqueous coatings may be applied to increasepalatability, improve elegance and stability or delay absorption.

Immediate Release Tablets/Capsules:

These are solid oral dosage forms made by conventional and novelprocesses. These units are taken orally without water for immediatedissolution and delivery of the medication. The active ingredient ismixed in a liquid containing ingredient such as sugar, gelatin, pectinand sweeteners. These liquids are solidified into solid tablets orcaplets by freeze drying and solid state extraction techniques. The drugcompounds may be compressed with viscoelastic and thermoelastic sugarsand polymers or effervescent components to produce porous matricesintended for immediate release, without the need of water.

Dose and Administration

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment of hyper-proliferative disorders and angiogenicdisorders, by standard toxicity tests and by standard pharmacologicalassays for the determination of treatment of the conditions identifiedabove in mammals, and by comparison of these results with the results ofknown medicaments that are used to treat these conditions, the effectivedosage of the compounds of this invention can readily be determined fortreatment of each desired indication. The amount of the activeingredient to be administered in the treatment of one of theseconditions can vary widely according to such considerations as theparticular compound and dosage unit employed, the mode ofadministration, the period of treatment, the age and sex of the patienttreated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, and in particular embodiments from about 0.01 mg/kg to about 20mg/kg body weight per day. Clinically useful dosing schedules will rangefrom one to three times a day dosing to once every four weeks dosing. Inaddition, “drug holidays” in which a patient is not dosed with a drugfor a certain period of time, may be beneficial to the overall balancebetween pharmacological effect and tolerability. A unit dosage maycontain from about 0.5 mg to about 1500 mg of active ingredient, and canbe administered one or more times per day or less than once a day. Theaverage daily dosage for administration by injection, includingintravenous, intramuscular, subcutaneous and parenteral injections, anduse of infusion techniques will in other embodiments be from 0.01 to 200mg/kg of total body weight. The average daily rectal dosage regimen willin particular embodiments be from 0.01 to 200 mg/kg of total bodyweight. The average daily vaginal dosage regimen will in otherembodiments be from 0.01 to 200 mg/kg of total body weight. The averagedaily topical dosage regimen will in still other embodiments be from 0.1to 200 mg administered between one to four times daily. The transdermalconcentration will in other embodiments be that required to maintain adaily dose of from 0.01 to 200 mg/kg. The average daily inhalationdosage regimen will in other embodiments be from 0.01 to 100 mg/kg oftotal body weight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

Combination Therapies

The compounds of this invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutical agents where the combination causes no unacceptableadverse effects. Those combined pharmaceutical agents can be otheragents having antiproliferative effects such as for example for thetreatment of haematological tumours, solid tumours and/or metastasesthereof and/or agents for the treatment of undesired side effects. Thepresent invention relates also to such combinations.

Other anti-hyper-proliferative agents suitable for use with thecomposition of the invention include but are not limited to thosecompounds acknowledged to be used in the treatment of neoplasticdiseases in Goodman and Gilman's The Pharmacological Basis ofTherapeutics (Ninth Edition), editor Molinoff et al., publ. byMcGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated byreference, especially (chemotherapeutic) anti-cancer agents as definedsupra. The combination can be a non-fixed combination or a fixed-dosecombination as the case may be.

Methods of testing for a particular pharmacological or pharmaceuticalproperty are well known to persons skilled in the art.

The example testing experiments described herein serve to illustrate thepresent invention and the invention is not limited to the examplesgiven.

As will be appreciated by persons skilled in the art, the invention isnot limited to the particular embodiments described herein, but coversall modifications of said embodiments that are within the spirit andscope of the invention as defined by the appended claims.

The following examples illustrate the invention in greater detail,without restricting it. Further compounds according to the invention, ofwhich the preparation is not explicitly described, can be prepared in ananalogous way.

The compounds, which are mentioned in the examples and the salts thereofrepresent preferred embodiments of the invention as well as a claimcovering all subcombinations of the residues of the compound of formula(I) as disclosed by the specific examples.

The term “according to” within the experimental section is used in thesense that the procedure referred to is to be used “analogously to”.

EXPERIMENTAL SECTION

Chemical names were generated using the ACD/Name software from ACD/Labs.In some cases generally accepted names of commercially availablereagents were used in place of ACD/Name generated names.

Table 1 lists the abbreviations used in this paragraph and in theExamples section as far as they are not explained within the text body.Other abbreviations have their meanings customary per se to the skilledperson.

TABLE 1 Abbreviations Abbreviation Meaning AcOH Acetic acid br broadsignal (NMR) d doublet (NMR) DAD Diode Array Detector DASTDiethylaminosulfur trifluoride DBU 1,8-Diazabicyclo(5.4.0)undec-7-eneDCM Dichloromethane dd doublet of doublet (NMR) DIPEADiisopropylethylamine DMA N,N-dimethylacetamide DMAP4-Dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethylsulfoxideEDC•HCl N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloridesalt ESI electrospray (ES) ionization EtOAc Ethyl acetate EtOH Ethanolh, hr (hrs) hour(s) HCl hydrogen chloride, hydrochloric acid HPLC highperformance liquid chromatography LC-MS liquid chromatography - massspectrometry m multiplet (NMR) MeCN Acetonitrile MeOH Methanol minminute(s) MS mass spectrometry MWD Multiple wavelength detector NMRNuclear Magnetic Resonance spectroscopy: chemical shifts (δ) are givenin ppm. The chemical shifts were corrected by setting the DMSO signal to2.50 ppm using unless otherwise stated. q quartet (NMR) Rt or RT roomtemperature R_(t), Rt retention time s singulet (NMR) SFC SupercriticalFluid Chromatography t triplet (NMR) td triplet of doublet (NMR) TEAtriethylamine TFA Trifluoroacetic acid THF tetrahydrofuran δ chemicalshift

Other abbreviations have their meanings customary per se to the skilledperson.

The various aspects of the invention described in this application areillustrated by the following examples which are not meant to limit theinvention in any way.

The example testing experiments described herein serve to illustrate thepresent invention and the invention is not limited to the examplesgiven.

Experimental Section—General Part

All reagents, for which the synthesis is not described in theexperimental part, are either commercially available, or are knowncompounds or may be formed from known compounds by known methods by aperson skilled in the art.

The compounds and intermediates produced according to the methods of theinvention may require purification. Purification of organic compounds iswell known to the person skilled in the art and there may be severalways of purifying the same compound. In some cases, no purification maybe necessary. In some cases, the compounds may be purified bycrystallization. In some cases, impurities may be removed by triturationusing a suitable solvent. In some cases, the compounds may be purifiedby chromatography, particularly flash column chromatography, using forexample prepacked silica gel cartridges, e.g. Biotage SNAP cartridgesKP-Sil® or KP-NH® in combination with a Biotage autopurifier system(SP4® or Isolera Four®) and eluents such as gradients of hexane/ethylacetate or DCM/methanol. In flash column chromatography, unmodified(“regular”) silica gel may be used as well as aminophase functionalizedsilica gel. If reference is made to flash column chromatography or toflash chromatography in the experimental section without specificationof a stationary phase, regular silica gel was used.

In some cases, the compounds may be purified by preparative HPLC usingfor example a Waters autopurifier equipped with a diode array detectorand/or on-line electrospray ionization mass spectrometer in combinationwith a suitable prepacked reverse phase column and eluents such asgradients of water and acetonitrile which may contain additives such astrifluoroacetic acid, formic acid or aqueous ammonia.

In some cases, purification methods as described above can provide thosecompounds of the present invention which possess a sufficiently basic oracidic functionality in the form of a salt, such as, in the case of acompound of the present invention which is sufficiently basic, atrifluoroacetate or formate salt for example, or, in the case of acompound of the present invention which is sufficiently acidic, anammonium salt for example. A salt of this type can either be transformedinto its free base or free acid form, respectively, by various methodsknown to the person skilled in the art, or be used as salts insubsequent biological assays. It is to be understood that the specificform (e.g. salt, free base etc.) of a compound of the present inventionas isolated and as described herein is not necessarily the only form inwhich said compound can be applied to a biological assay in order toquantify the specific biological activity.

Analytical LC-MS Methods:

Method 1:

Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEHC18 1.7 μm, 50×2.1 mm; eluent A: water+0.1 vol % formic acid (99%),eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B;flow 0.8 ml/min; temperature: 60° C.; DAD scan: 210-400 nm.

Method 2:

Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEHC18 1.7 μm, 50×2.1 mm; eluent A: water+0.2 vol % aqueous ammonia (32%),eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B;flow 0.8 ml/min; temperature: 60° C.; DAD scan: 210-400 nm.

Method 3:

Instrument: Waters Acquity UPLC H-Class system; Column: Acquity CSH C181.7 μm 2.1×50 mm; eluent A: water+0.1 vol % formic acid, eluent B:acetonitrile, eluent C: 2 vol % ammonia (28%) in water, eluent D: 2 vol% formic acid in water; gradient: 0-1.2 min 2-95% B with A and 5% Dthroughout, 1.2-1.4 min 95% B; flow 0.8 ml/min; temperature: 40° C.;PDA: 215-350 nm.

Method 4:

Instrument: Waters Acquity UPLC H-Class system; Column: XBridge BEH C182.5 μm 2.1×50 mm; eluent A: water+0.1 vol % formic acid, eluent B:acetonitrile, eluent C: 2 vol % ammonia (28%) in water, eluent D: 2 vol% formic acid in water; gradient: 0-1.2 min 2-95% B with A and 5% Cthroughout, 1.2-1.4 min 95% B; flow 0.8 ml/min; temperature: 40° C.;PDA: 215-350 nm.

Method 5:

MS instrument: SHIMADZU LCMS-2020; HPLC instrument: LabSolution Version5.72; Column: Kinetex@5 um EVO C18 30×2.1 mm; eluent A: 0.0375% TFA inwater (v/v), eluent B: 0.01875% TFA in acetonitrile: gradient: 0.0 min0% B 3.00 min 60% B 3.50 min 60% B 3.51 min 0% B 4.00 min 0% B; flowrate: 0.8 mL/mix; oven temperature: 50° C.; UV detection: 220 nm & 254nm.

Method 9:

Instrument: Agilent HPLC 1260; Column: Amylose SA 3μ 100×4.6 mm; EluentA: Acetonitrile+0.1 Vol-% Diethylamine (99%); Eluent B: Ethanol;Isocratic: 90% A+10% B; Flow 1.4 ml/min; Temperature: 25° C.; DAD 220 nm

Method 10:

Instrument: Agilent 1290 UPLCMS 6230 TOF; column: BEH C 18 1.7 μm,50×2.1 mm; Eluent A: water+0.05% formic acid (99%); Eluent B:acetonitrile+0.05% formic acid (99%); gradient: 0-1.7 2-90% B, 1.7-2.090% B; flow 1.2 ml/min; temperature: 60° C.; DAD scan: 190-400 nm.

Method 11:

Column: CSH C18 1.7 μm 2.1×50 mm, Waters Acquity Quaternary pump (Flow0.8 mL/min), Waters Acquity Autosampler, Waters Acquity QDA, WatersAcquity PDA, Waters Acquity ELSD, UV DAD: 215-350 nm, run time: 4.60mins, solvents A) water B) acetonitrile D) 2% formic acid: the gradientruns with 5% D, Gradient: 2-95% B with A and 5% D 4.0 mins, hold at 95%B 5% D to 4.60 min @ 0.8 ml/min, 40° C.

Preparative LC-MS Methods:

Method 6:

Instrument: Waters Autopurification MS SingleQuad; Column: WatersXBrigde C18 5μ 100×30 mm; eluent A: water+0.2 vol % aqueous ammonia(32%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70ml/min; temperature: 25° C.; DAD scan: 210-400 nm

Method 7:

Instrument: pump: Labomatic HD-5000 or HD-3000, head HDK 280,lowpressure gradient module ND-B1000; manual injection valve: Rheodyne3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic LabocolVario-4000; column: Chromatorex RP C-18 10 μm, 125×30 mm; solvent A:water+0.1 vol-% formic acid, solvent B: acetonitrile; gradient:0.00-0.50 min 30% B (150 ml/min), 0.50-6.00 min 30-70% B (150 ml/min),6.00-6.10 min 70-100% B (150 ml/min), 6.10-8.00 min 100% B (150 ml/min);UV-Detection.

Method 8:

Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario4000, Column: Amylose SA 5p 250×30 mm; Eluent A: Acetonitrile+0.1 Vol-%Diethylamine (99%); Eluent B: Ethanol; Isocratic: 90% A+10% B; Flow 50.0ml/min; UV 220 nm

NMR Spectra:

The multiplicities of proton signals in ¹H NMR spectra given in thefollowing paragraphs reflect the observed signal form and do not takeinto account any higher-order signal phenomena. As a rule, the chemicalshift data refers to the center of the signal in question. In the caseof wide multiplets, a range is specified. Signals hidden by solvent orwater were either assigned tentatively or are not listed. Stronglybroadened signals—e.g. caused by rapid rotation of molecular moieties orby interchanging protons—have also been assigned tentatively (oftenreferred to as a broad multiplet or broad singlet) or are not shown.

The ¹H-NMR data of selected compounds are listed in the form of ¹H-NMRpeaklists. Therein, for each signal peak the δ value in ppm is given,followed by the signal intensity, reported in round brackets. The δvalue-signal intensity pairs from different peaks are separated bycommas. Therefore, a peaklist is described by the general form: δ₁(intensity₁), δ₂ (intensity₂), . . . , δ_(i) (intensity_(i)), . . . ,δ_(n) (intensity_(n)).

The intensity of a sharp signal correlates with the height (in cm) ofthe signal in a printed NMR spectrum. When compared with other signals,this data can be correlated to the real ratios of the signalintensities. In the case of broad signals, more than one peak, or thecenter of the signal along with their relative intensity, compared tothe most intense signal displayed in the spectrum, are shown. A ¹H-NMRpeaklist is similar to a classical ¹H-NMR readout, and thus usuallycontains all the peaks listed in a classical NMR interpretation.Moreover, similar to classical ¹H-NMR printouts, peaklists can showsolvent signals, signals derived from stereoisomers of the particulartarget compound, peaks of impurities, ¹³C satellite peaks, and/orspinning sidebands. The peaks of stereoisomers, and/or peaks ofimpurities are typically displayed with a lower intensity compared tothe peaks of the target compound (e.g., with a purity of >90%). Suchstereoisomers and/or impurities may be typical for the particularmanufacturing process, and therefore their peaks may help to identify areproduction of the manufacturing process on the basis of “by-productfingerprints”. An expert who calculates the peaks of the target compoundby known methods (MestReC, ACD simulation, or by use of empiricallyevaluated expectation values), can isolate the peaks of the targetcompound as required, optionally using additional intensity filters.Such an operation would be similar to peak-picking in classical ¹H-NMRinterpretation. A detailed description of the reporting of NMR data inthe form of peaklists can be found in the publication “Citation of NMRPeaklist Data within Patent Applications” (cf.http://www.researchdisclosure.com/searching-disclosures, ResearchDisclosure Database Number 605005, 2014, 1 Aug. 2014). In the peakpicking routine, as described in the Research Disclosure Database Number605005, the parameter “MinimumHeight” can be adjusted between 1% and 4%.However, depending on the chemical structure and/or depending on theconcentration of the measured compound it may be reasonable to set theparameter “MinimumHeight”<1%.

Syntheses of Intermediates Syntheses of Intermediate 1 CompoundsIntermediate 1-1 3-(2-hydroxy-2-methylpropoxy)pyridine-4-carbonitrile

To an ice-cooled solution of 2-methylpropane-1,2-diol (3.20 g, 35.5mmol) in DMF (62 ml) under an argon atmosphere was added NaH 60%dispersion on mineral oil (1.36 g, 34.0 mmol) slowly portionwise. Thereaction mixture was stirred with ice-cooling for 30 min and3-chloropyridine-4-carbonitrile (4.10 g, 29.6 mmol) was added. Thereaction was allowed to warm slowly to RT and stirred at thistemperature for 2 h. The reaction mixture was poured on an ice-watermixture and extracted with EtOAc. The organics were combined and washedwith water, filtered through a hydrophobic filter and concentrated. Theresidue was purified by silica chromatography (hexane:EtOAc) to give thetitle compound (2 g, 35% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.72 (s, 1H), 8.38 (d, 1H), 7.78 (d,1H), 4.77 (s, 1H), 4.04-4.11 (m, 2H), 1.16-1.25 (m, 6H).

Intermediate 1-2 3-(2-methoxy-2-methylpropoxy)pyridine-4-carbonitrile

According to the method described for Intermediate 1-1 and using2-methoxy-2-methylpropan-1-ol as a starting material, the title compoundwas prepared (18.77 g, 88% yield).

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm]=8.72 (s, 1H), 8.38 (d, 1H), 7.78 (d,1H), 4.19 (s, 2H), 3.15-3.22 (m, 3H), 1.24 (s, 6H).

Intermediate 1-33-[2-methyl-2-(morpholin-4-yl)propoxy]pyridine-4-carbonitrile

To an ice-cooled solution of 2-methyl-2-(morpholin-4-yl)propan-1-ol(4.00 g, 25.1 mmol) in THF (12.5 ml) under an argon atmosphere was addedNaH 60% dispersion on mineral oil (1.1 g, 27.4 mmol) slowly portionwise.The reaction mixture was stirred with ice-cooling for 1 h and a solutionof 3-chloropyridine-4-carbonitrile (4.10 g, 29.6 mmol) in THF (64.5 ml)was added. The reaction was allowed to warm slowly to RT and stirred atthis temperature for 16 h. The reaction was then heated under refluxconditions for 2 h. The reaction mixture was quenched with a sat. NH4Clsolution and extracted with EtOAc. The organics were combined and washedwith sat. NaCl, filtered through a hydrophobic filter and concentrated.The residue was crystallized with MTBE and collected by filtration togive the title compound (2 g, 35% yield) which was used without furtherpurification.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.75 (s, 1H), 8.38 (d, 1H), 7.78 (d,1H), 4.19 (s, 2H), 3.44-3.52 (m, 4H), 2.57-2.62 (m, 4H), 1.10-1.23 (m,6H).

Intermediate 1-43-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}pyridine-4-carbonitrile

According to the method described for Intermediate 1-3 and using[(2S)-1-methylpyrrolidin-2-yl]methanol (3.50 g, 30.4 mmol) as a startingmaterial, the title compound was prepared (4.03 g, 67% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.71 (s, 1H), 8.38 (d, 1H), 7.77 (d,1H), 4.23 (d, 2H), 2.93-2.99 (m, 1H), 2.60-2.70 (m, 1H), 2.39 (s, 3H),2.22 (q, 1H), 1.92-2.02 (m, 1H), 1.60-1.78 (m, 3H).

Intermediate 1-57 3-(3-methoxy-3-methylbutoxy)pyridine-4-carbonitrile

To a solution of 3-methoxy-3-methylbutan-1-ol (4.00 g, 33.8 mmol) in 39ml. THF sodium hydride (1.30 g, 60% purity, 32.4 mmol) was addedportionswise at 0° C. and the suspension was stirred for 39 minutes atrt. Then 3-chloropyridine-4-carbonitrile (3.91 g, 28.2 mmol) solved in78 ml. THF was added dropwise and the reaction mixture was stirredovernight at rt. The solution was diluted carefully with water andextracted with a mixture of dichloromethane and of methanol (9:1) threetimes. The combined organic layers were filtered through awaterresistant filter and the filtrate was concentrated under reducedpressure. The residue was purified by flash chromatography to give 4.30g of the title compound (97% purity, 67% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.074 (2.43), 1.188 (16.00), 1.960(0.99), 1.978 (2.12), 1.995 (1.02), 3.056 (1.64), 3.121 (11.50), 4.330(1.11), 4.347 (2.36), 4.364 (1.10), 7.766 (1.21), 7.768 (1.30), 7.778(1.25), 7.780 (1.37), 8.370 (1.60), 8.382 (1.54), 8.720 (2.00).

LC-MS (method 2): R, =0.97 min; MS (ESIpos): m/z=221 [M+H]⁺

Intermediate 1-58 3-(2-ethoxy-2-methylpropoxy)pyridine-4-carbonitrile

According to the method described for Intermediate 1-57 and using2-ethoxy-2-methylpropan-1-ol (1.00 g, 8.46 mmol) as a starting material,the title compound was prepared 770 mg (98% purity, 49% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.994 (2.41), 1.011 (5.70), 1.029(2.49), 1.041 (0.53), 1.249 (16.00), 3.410 (0.79), 3.427 (2.60), 3.445(2.54), 3.462 (0.75), 4.192 (4.92), 7.766 (1.29), 7.768 (1.32), 7.778(1.30), 7.780 (1.37), 8.372 (1.71), 8.384 (1.64), 8.732 (2.12).

LC-MS (method 2): R_(t)=0.99 min; MS (ESIpos): m/z=221 [M+H]⁺

Intermediate 1-603-[2-(dimethylamino)-2-methylpropoxy]pyridine-4-carbonitrile

According to the method described for Intermediate 1-57 and using2-(dimethylamino)-2-methylpropan-1-ol (4.00 g, 34.1 mmol) as a startingmaterial, the title compound was prepared 6.30 g (93% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.035 (1.39), 1.052 (2.99), 1.070(1.46), 1.119 (15.82), 2.240 (16.00), 2.518 (1.42), 2.522 (0.99), 3.422(0.71), 3.435 (0.74), 3.440 (0.68), 3.452 (0.69), 4.157 (4.81), 4.342(0.50), 4.355 (0.95), 4.368 (0.47), 5.758 (0.40), 7.767 (1.21), 7.779(1.27), 8.373 (1.68), 8.385 (1.63), 8.738 (2.31). LC-MS (method 2):R_(t)=0.90 min; MS (ESIpos): m/z=220 [M+H]⁺

Intermediate 1-633-{[1-methylpiperidin-2-yl]methoxy}pyridine-4-carbonitrile

According to the method described for Intermediate 1-57 and using(1-methylpiperidin-2-yl)methanol (11 ml, 87 mmol) as a startingmaterial, the title compound was prepared 11.5 g (95% purity, 65%yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.239 (0.49), 1.270 (0.60), 1.345(0.53), 1.348 (0.52), 1.353 (0.51), 1.371 (0.50), 1.380 (0.57), 1.432(0.43), 1.461 (0.61), 1.531 (0.59), 1.537 (0.45), 1.689 (0.49), 1.717(0.44), 1.720 (0.44), 1.768 (0.52), 1.772 (0.53), 1.775 (0.49), 1.779(0.45), 1.800 (0.43), 1.807 (0.41), 2.014 (0.52), 2.022 (0.59), 2.043(1.06), 2.050 (1.07), 2.071 (0.56), 2.079 (0.51), 2.254 (16.00), 2.268(0.58), 2.273 (0.61), 2.280 (0.51), 2.743 (0.64), 2.746 (0.64), 2.772(0.60), 2.774 (0.59), 4.194 (0.98), 4.207 (0.98), 4.219 (1.31), 4.232(1.24), 4.356 (1.28), 4.368 (1.31), 4.381 (0.98), 4.394 (0.96), 7.768(2.20), 7.780 (2.36), 8.375 (3.15), 8.387 (3.05), 8.729 (3.99).

LC-MS (method 2): R_(t)=0.92 min; MS (ESIpos): m/z=232 [M+H]⁺

Intermediate 1-65 3-[(oxolan-3-yl)methoxy]pyridine-4-carbonitrile

To a solution of 3-chloroisonicotinonitrile (1.23 g, 8.90 mmol) and(oxolan-3-yl)methanol (1.00 g, 9.79 mmol) in 40 ml.2-methyltetrahydrofurane was added potassium tert-butoxide (1.20 g, 10.7mmol) and the mixture was stirred for 4 h at rt. The reaction mixturewas diluted slowly with a aqueous solution of ammonium chloride andextracted with ethyl acetate three times. The combined organic layer waswashed with brine, dried over sodium sulfate, filtered and the filtratewas concentrated under reduced pressure. The residue was purified byflash chromatography to give 1.34 g of the title compound (74% yield,90% purity).

1H NMR (400 MHz, CDCl3): d [ppm]=1.75-1.87 (m, 1H), 2.13-2.30 (m, 1H),2.78-2.95 (m, 1H), 3.74-3.87 (m, 2H), 3.90-4.00 (m, 2H), 4.11-4.21 (m,2H), 7.48 (d, 1H), 8.40 (d, 1H), 8.50 (s, 1H).

UPLC-MS (method 4): Rt=0.57 min., 94%. MS (ESIpos): m/z=(M+H)+222

Intermediate 1-66 3-{[(2S)-oxolan-2-yl]methoxy}pyridine-4-carbonitrile

According to the method described for Intermediate 1-57 and using[(2S)-oxolan-2-yl]methanol (1.00 g, 9.79 mmol) as a starting material,the title compound was prepared 1.71 g (99% purity, 85% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (2.31), 1.172 (4.65), 1.190(2.40), 1.700 (0.67), 1.716 (1.62), 1.720 (1.19), 1.729 (1.38), 1.731(1.35), 1.736 (2.07), 1.745 (2.56), 1.749 (1.39), 1.753 (1.52), 1.761(1.81), 1.765 (2.68), 1.782 (1.96), 1.788 (0.78), 1.805 (1.06), 1.817(1.15), 1.824 (1.48), 1.833 (1.88), 1.838 (1.69), 1.841 (1.45), 1.854(2.48), 1.871 (2.12), 1.888 (1.38), 1.902 (1.61), 1.909 (0.84), 1.919(2.04), 1.934 (1.89), 1.938 (1.69), 1.949 (1.19), 1.952 (1.13), 1.955(1.41), 1.964 (0.76), 1.969 (1.02), 1.983 (2.72), 1.987 (9.66), 2.000(2.04), 2.010 (1.89), 2.015 (1.57), 2.020 (1.52), 2.024 (1.46), 2.031(1.86), 2.043 (1.46), 2.049 (1.19), 2.062 (0.82), 2.331 (0.56), 2.518(3.41), 2.522 (2.11), 2.673 (0.58), 3.664 (1.92), 3.684 (3.84), 3.700(4.51), 3.702 (3.81), 3.718 (2.78), 3.769 (2.68), 3.785 (5.28), 3.789(2.72), 3.802 (3.67), 3.806 (3.47), 3.822 (1.96), 3.999 (0.68), 4.017(2.07), 4.035 (2.07), 4.053 (0.70), 4.189 (0.87), 4.198 (1.10), 4.204(1.82), 4.213 (2.20), 4.220 (2.49), 4.229 (2.98), 4.238 (1.78), 4.244(6.81), 4.257 (1.50), 4.269 (8.40), 4.283 (5.50), 4.319 (6.52), 4.327(6.36), 4.344 (3.74), 4.353 (2.58), 7.770 (8.92), 7.782 (9.31), 8.373(11.59), 8.385 (11.19), 8.708 (16.00).

LC-MS (method 2): R_(t)=0.80 min; MS (ESIpos): m/z=205 [M+H]⁺

Intermediate 1-67 3-{[(2R)-oxolan-2-yl]methoxy}pyridine-4-carbonitrile

According to the method described for Intermediate 1-57 and using[(2R)-oxolan-2-yl]methanol (1.00 g, 9.79 mmol) as a starting material,the title compound was prepared 1.57 g (99% purity, 78% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (2.06), 1.172 (4.29), 1.189(2.16), 1.700 (0.68), 1.716 (1.63), 1.720 (1.21), 1.729 (1.40), 1.731(1.39), 1.736 (2.09), 1.745 (2.55), 1.749 (1.45), 1.753 (1.52), 1.761(1.81), 1.765 (2.68), 1.782 (1.91), 1.788 (0.78), 1.805 (1.07), 1.817(1.15), 1.823 (1.49), 1.833 (1.91), 1.837 (1.74), 1.841 (1.48), 1.853(2.53), 1.871 (2.12), 1.887 (1.32), 1.902 (1.65), 1.909 (0.86), 1.918(2.12), 1.934 (1.92), 1.938 (1.73), 1.949 (1.23), 1.954 (1.39), 1.964(0.79), 1.968 (1.07), 1.983 (2.84), 1.986 (8.32), 2.000 (2.06), 2.010(1.92), 2.020 (1.54), 2.024 (1.49), 2.031 (1.93), 2.043 (1.49), 2.049(1.18), 2.062 (0.77), 2.518 (1.73), 2.522 (1.06), 3.664 (1.87), 3.684(3.92), 3.700 (4.46), 3.718 (2.71), 3.769 (2.70), 3.785 (5.37), 3.802(3.64), 3.806 (3.51), 3.822 (1.94), 3.999 (0.62), 4.016 (1.88), 4.034(1.86), 4.052 (0.74), 4.189 (0.86), 4.198 (1.12), 4.205 (1.89), 4.213(2.25), 4.220 (2.57), 4.229 (3.07), 4.238 (1.83), 4.243 (6.71), 4.257(1.42), 4.269 (8.22), 4.283 (5.52), 4.318 (6.39), 4.327 (6.34), 4.344(3.72), 4.352 (2.60), 7.770 (8.53), 7.783 (8.91), 8.372 (11.38), 8.384(10.95), 8.708 (16.00).

LC-MS (method 2): R_(t)=0.80 min; MS (ESIpos): m/z=205 [M+H]⁺

Intermediate 1-68 3-[(oxan-2-yl)methoxy]pyridine-4-carbonitrile

According to the method described for Intermediate 1-57 and using(oxan-2-yl)methanol (4.00 g, 98% purity, 33.7 mmol) as a startingmaterial, the title compound was prepared 4.44 g (99% purity, 60%yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.317 (0.67), 1.327 (0.58), 1.347(2.01), 1.357 (1.66), 1.376 (2.31), 1.379 (2.27), 1.385 (2.15), 1.399(0.91), 1.407 (2.07), 1.416 (2.07), 1.422 (2.00), 1.432 (2.43), 1.438(1.54), 1.454 (2.00), 1.463 (2.87), 1.473 (3.60), 1.481 (6.00), 1.488(6.43), 1.503 (2.42), 1.512 (3.34), 1.521 (1.76), 1.533 (1.58), 1.543(1.96), 1.553 (1.37), 1.573 (0.60), 1.643 (2.27), 1.649 (2.31), 1.678(1.99), 1.757 (0.58), 1.773 (0.43), 1.813 (2.16), 1.842 (1.42), 1.907(1.48), 2.331 (0.61), 2.518 (4.00), 2.522 (2.49), 3.200 (0.40), 3.209(0.63), 3.214 (0.94), 3.222 (0.73), 3.228 (0.72), 3.233 (0.84), 3.241(1.31), 3.253 (0.75), 3.256 (1.12), 3.268 (0.84), 3.278 (0.43), 3.299(1.01), 3.306 (1.13), 3.317 (1.96), 3.343 (1.42), 3.364 (1.69), 3.374(1.87), 3.392 (2.78), 3.400 (3.57), 3.419 (1.76), 3.428 (1.88), 3.651(1.04), 3.656 (1.19), 3.665 (1.97), 3.669 (1.70), 3.680 (1.96), 3.693(1.87), 3.703 (1.19), 3.709 (1.06), 3.821 (0.66), 3.830 (0.58), 3.849(0.51), 3.854 (0.58), 3.875 (2.31), 3.879 (2.81), 3.884 (2.03), 3.903(2.12), 3.907 (2.13), 3.913 (1.94), 4.241 (0.79), 4.257 (16.00), 4.267(9.01), 4.272 (8.57), 4.298 (0.64), 4.522 (1.30), 4.537 (2.06), 4.551(0.91), 7.766 (8.21), 7.778 (8.57), 8.370 (10.48), 8.382 (10.13), 8.710(15.12).

LC-MS (method 2): R_(t)=0.94 min; MS (ESIpos): m/z=219 [M+H]⁺

Intermediate 1-80 tert-butyl(2S)-2-{[(4-cyanopyridin-3-yl)oxy]methyl}pyrrolidine-1-carboxylate

According to the method described for Intermediate 1-57 and usingtert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (4.00 g, 19.9mmol) as a starting material, the title compound was prepared 4.02 g(74% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (1.08), 1.172 (2.07), 1.190(0.95), 1.376 (14.20), 1.383 (16.00), 1.808 (0.85), 1.816 (0.68), 1.834(0.40), 1.839 (0.40), 1.921 (0.85), 1.928 (0.98), 1.941 (0.57), 1.948(0.53), 1.956 (0.52), 1.988 (4.17), 2.024 (1.33), 2.332 (0.67), 2.518(3.50), 2.523 (2.43), 2.673 (0.68), 3.273 (1.02), 3.282 (1.48), 3.292(1.80), 3.300 (1.93), 4.017 (0.85), 4.035 (0.87), 4.053 (0.62), 4.067(0.93), 4.073 (1.02), 4.079 (0.97), 4.285 (0.43), 4.302 (0.53), 4.337(1.67), 4.353 (0.82), 4.420 (0.42), 4.440 (0.40), 7.775 (0.85), 7.787(1.48), 8.390 (1.52), 8.748 (7.37).

LC-MS (method 2): R, =1.17 min; MS (ESIpos): m/z=304 [M+H]⁺

Intermediate 1-81 3-[2-(morpholin-4-yl)ethoxy]pyridine-4-carbonitrile

To a solution of 2-(morpholin-4-yl)ethan-1-ol, 500 mg (3.81 mmol), intetrahydrofuran, 4.40 mL, was added sodium hydride (60% in oil), 191 mg(4.76 mmol). After stirring at room temperature for 1 hour,3-chloropyridine-4-carbonitrile, 440 mg (3.18 mmol), in tetrahydrofuran,4.40 mL, was added. After stirring at room temperature for 18 hours, thereaction was quenched with water, extracted with ethyl acetate, theorganic layers were dried over magnesium sulfate, filtered andconcentrated in vacuo. Trituration with heptane gave3-[2-(morpholin-4-yl)ethoxy]pyridine-4-carbonitrile, 695 mg (94%). ¹HNMR (400 MHz, CDCl₃): δ [ppm]=2.58-2.66 (m, 4H), 2.89 (t, 2H), 3.67-3.75(m, 4H), 4.35 (t, 2H), 7.44 (d, 1H), 8.37 (d, 1H), 8.49 (s, 1H);

LC-MS (method 3): R, =0.50 min., 88%. MS (ESIpos): m/z=(M+H)+234.

Intermediate 1-82 3-[(oxan-4-yl)methoxy]pyridine-4-carbonitrile

To a solution of 3-chloroisonicotinonitrile (618 mg, 4.46 mmol) andtetrahydro-2H-pyran-4-ylmethanol (570 mg, 4.91 mmol) in 2-MeTHF (25 mL)was added KOtBu (601 mg, 5.35 mmol) and the mixture stirred at roomtemperature for 4 h. TLC showed mostly product. The mixture was dilutedslowly with water and extracted with EtOAc, washed with brine, driedover sodium sulfate, filtered and concentrated under reduced pressure togive the title compound (960 mg (99% yield) as a pale yellow oil.

1H NMR (400 MHz, CDCl₃): d [ppm]=1.44-1.56 (m, 2H), 1.78-1.88 (m, 2H),2.14-2.39 (m, 1H), 3.36-3.57 (m, 4H), 4.08 (d, 2H), 7.46 (d, 1H), 8.40(d, 1H), 8.50 (s, 1H).

LC-MS (Method 4): Rt=0.63 min., 86%. MS (ESIpos): m/z=(M+H)+218

Intermediate 1-96 tert-butyl{2-[(4-cyanopyridin-3-yl)oxy]ethyl}methylcarbamate

According to the method described for Intermediate 1-57 and using[tert-butyl (2-hydroxyethyl)methylcarbamate (15.2 g, 86.6 mmol) as astarting material, the title compound was prepared 19.1 g (95% yield).

LC-MS (method 2): R_(t)=1.07 min; MS (ESIpos): m/z=278 [M+H]⁺

Syntheses of Intermediate 2 Compounds Intermediate 2-11-{[4-(aminomethyl)pyridin-3-yl]oxy}-2-methylpropan-2-ol

An autoclave was charged with3-(2-hydroxy-2-methylpropoxy)pyridine-4-carbonitrile (2.00 g, 10.4mmol), ammonia (36 ml, 7.0 M in methanol) and Raney-Nickel (1.53 g, 50%wet) and the mixture was stirred under 25 bar hydrogen atmosphere at RTfor 20 h. For the work-up, the mixture was filtered through a pad ofcelite, eluted with methanol and the combined filtrates wereconcentrated under reduced pressure. The residue was used directly inthe next step without further purification (2 g, 98% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.12-8.25 (m, 2H), 7.38 (d, 1H),4.52-5.06 (m, 1H), 3.84 (s, 2H), 3.66-3.81 (m, 2H), 1.84 (brs, 1H),1.17-1.26 (m, 6H).

Intermediate 2-21-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methanamine

According to the method described for Intermediate 2-1 and using3-(2-methoxy-2-methylpropoxy)pyridine-4-carbonitrile as a startingmaterial, the title compound was prepared (18.3 g, 99% yield)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.24 (br s, 1H), 8.17 (br d, 1H),7.33-7.44 (m, 1H), 3.97 (s, 2H), 3.71 (brs, 2H), 3.16 (s, 3H), 1.80(brs, 2H), 1.22 (s, 6H).

Intermediate 2-31-{3-[2-methyl-2-(morpholin-4-yl)propoxy]pyridin-4-yl}methanamine

According to the method described for Intermediate 2-1 and using3-[2-methyl-2-(morpholin-4-yl)propoxy]pyridine-4-carbonitrile as astarting material, the title compound was prepared (3.07 g, 89% yield)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.24 (s, 1H), 8.16 (d, 1H), 7.37 (d,1H), 3.97 (s, 2H), 3.72 (s, 2H), 3.50-3.56 (m, 4H), 2.55-2.61 (m, 4H),1.87 (brs, 2H), 1.05-1.15 (m, 6H).

Intermediate 2-41-(3-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}pyridin-4-yl)methanamine

According to the method described for Intermediate 2-1 and using3-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}pyridine-4-carbonitrile (4.71g, 21.7 mmol) as a starting material, the title compound was prepared(4.60 g, 96% yield)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.24 (s, 1H), 8.16 (d, 1H), 7.38 (d,1H), 4.08 (m, 1H), 3.95 (m, 1H), 3.62-3.78 (m, 2H), 2.91-3.00 (m, 1H),2.58 (dq, 1H), 2.34-2.39 (m, 3H), 2.20 (q, 1H), 1.56-2.08 (m, 6H).

Intermediate 2-581-[3-(2-ethoxy-2-methylpropoxy)pyridin-4-yl]methanamine

According to the method described for intermediate 2-57 and using3-(2-ethoxy-2-methylpropoxy)pyridine-4-carbonitrile (intermediate 1-58,770 mg, 3.50 mmol) as a starting material, the title compound wasprepared 250 mg (99% purity, 60% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.970 (0.66), 1.013 (0.72), 1.026(3.44), 1.031 (0.73), 1.035 (0.55), 1.043 (7.38), 1.061 (3.55), 1.206(3.67), 1.222 (7.65), 1.236 (16.00), 1.258 (0.80), 1.264 (0.54), 1.295(0.44), 1.352 (0.48), 2.518 (1.02), 2.522 (0.63), 3.384 (0.46), 3.388(0.46), 3.399 (1.15), 3.406 (0.47), 3.417 (3.18), 3.434 (3.31), 3.452(1.08), 3.713 (2.29), 3.958 (2.52), 3.963 (4.45), 3.985 (0.56), 4.061(0.49), 4.543 (0.52), 4.554 (0.53), 7.367 (0.80), 7.380 (1.09), 8.156(1.08), 8.167 (1.08), 8.190 (0.69), 8.202 (0.67), 8.234 (1.85), 8.247(0.94).

LC-MS (method 2): R, =0.75 min; MS (ESIpos): m/z=225 [M+H]⁺

Intermediate 2-601-{[4-(aminomethyl)pyridin-3-yl]oxy}-N,N,2-trimethylpropan-2-amine

According to the method described for intermediate 2-57 and using3-[2-(dimethylamino)-2-methylpropoxy]pyridine-4-carbonitrile(intermediate 1-60, 6.30 g, 28.7 mmol) as a starting material, the titlecompound was prepared (additional a flash chromatography) 5.12 g (80%yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.020 (1.05), 1.099 (14.49), 2.133(1.17), 2.225 (16.00), 2.518 (1.04), 2.523 (0.73), 3.712 (1.47), 3.943(4.03), 7.370 (0.51), 7.382 (0.53), 8.153 (1.27), 8.164 (1.27), 8.243(2.05).

LC-MS (method 2): R_(t)=0.69 min; MS (ESIpos): m/z=224 [M+H]⁺

Intermediate 2-631-{3-[(1-methylpiperidin-2-yl)methoxy}pyridin-4-yl}methanamine

According to the method described for intermediate 2-57 and using3-[(1-methylpiperidin-2-yl)methoxy]pyridine-4-carbonitrile (Intermediate1-63, 12.8 g, 55.4 mmol) as a starting material, the title compound wasprepared 12.9 g (95% purity, 94% yield).

LC-MS (method 2): R_(t)=0.72 min; MS (ESIpos): m/z=236[M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.223 (0.41), 1.233 (0.72), 1.242(0.49), 1.254 (0.53), 1.263 (0.77), 1.272 (0.52), 1.293 (0.43), 1.355(0.73), 1.381 (0.62), 1.389 (0.73), 1.411 (0.44), 1.422 (0.52), 1.433(0.63), 1.454 (0.47), 1.463 (0.74), 1.473 (0.47), 1.528 (0.94), 1.560(0.49), 1.684 (0.88), 1.744 (1.78), 1.768 (1.16), 1.998 (0.64), 2.006(0.72), 2.027 (1.25), 2.035 (1.25), 2.055 (0.68), 2.062 (0.64), 2.123(0.45), 2.128 (0.47), 2.186 (0.75), 2.193 (0.81), 2.209 (1.16), 2.228(16.00), 2.518 (0.92), 2.522 (0.58), 2.744 (0.95), 2.773 (0.88), 3.333(10.42), 3.766 (0.57), 3.987 (0.80), 3.998 (0.89), 4.012 (1.10), 4.024(1.06), 4.159 (1.02), 4.171 (1.09), 4.185 (0.86), 4.195 (0.83), 7.370(0.95), 7.378 (0.98), 8.165 (0.98), 8.245 (1.23).

LC-MS (method 2): R, =0.72 min; MS (ESIpos): m/z=236[M+H]⁺

Intermediate 2-65 1-{3-[(oxolan-3-yl)methoxy]pyridin-4-yl}methanamine

To a solution of 3-[(oxolan-3-yl)methoxy]pyridine-4-carbonitrile(intermediate 1-65, 500 mg, 2.45 mmol) in 30 mL methanol was addedpalladium on carbon (10%, slurried in 0.1 ml. toluene) and the mixtureplaced under an atmosphere of hydrogen and stirred 4 days at roomtemperature. Filtered through a plug of celite, washing with methanol.The filtrate was concentrated under reduced pressure to give the desiredproduct 530 mg

LC-MS (method 4): Rt=0.43 min., >66%. MS (ESIpos): m/z=(M+H)+209.

Intermediate 2-661-(3-{[(2S)-oxolan-2-yl]methoxy}pyridin-4-yl)methanamine

According to the method described for Intermediate 2-57 and using3-{[(2S)-oxolan-2-yl]methoxy}pyridine-4-carbonitrile (intermediate 1-66,1.71 g, 8.37 mmol) as a starting material, the title compound wasprepared 1.51 g (93% purity, 81% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.676 (1.30), 1.692 (2.52), 1.713(3.36), 1.721 (3.46), 1.726 (2.85), 1.729 (2.81), 1.737 (2.99), 1.742(3.99), 1.759 (3.23), 1.783 (2.99), 1.801 (3.62), 1.813 (3.49), 1.819(3.58), 1.829 (4.08), 1.850 (4.83), 1.867 (5.48), 1.883 (4.41), 1.898(2.94), 1.903 (2.89), 1.919 (2.07), 1.933 (1.32), 1.948 (0.92), 1.962(2.14), 1.981 (2.86), 1.993 (2.94), 2.002 (2.40), 2.005 (2.30), 2.011(2.71), 2.024 (2.06), 2.044 (1.06), 2.323 (0.56), 2.327 (0.75), 2.332(0.56), 2.665 (0.56), 2.669 (0.75), 2.673 (0.54), 3.634 (0.62), 3.661(3.32), 3.681 (16.00), 3.697 (7.84), 3.715 (3.51), 3.742 (0.76), 3.760(3.36), 3.770 (2.03), 3.777 (6.40), 3.796 (4.67), 3.814 (2.14), 4.014(2.86), 4.028 (3.51), 4.039 (5.48), 4.053 (6.30), 4.090 (5.63), 4.099(6.81), 4.116 (3.25), 4.124 (4.01), 4.152 (2.09), 4.168 (3.44), 4.178(3.29), 4.183 (3.37), 4.193 (2.77), 4.209 (1.42), 4.220 (0.73), 4.228(0.70), 4.244 (0.77), 4.269 (0.62), 4.283 (0.52), 4.296 (0.47), 4.304(0.43), 4.319 (0.71), 4.327 (0.62), 7.373 (4.73), 7.384 (4.89), 7.407(0.52), 7.419 (0.41), 7.605 (0.45), 7.617 (0.47), 7.771 (0.47), 7.784(0.46), 8.158 (5.39), 8.169 (5.59), 8.235 (8.50), 8.272 (1.00), 8.297(0.64), 8.309 (0.63), 8.373 (0.55), 8.385 (0.54), 8.472 (0.45), 8.549(0.84), 8.709 (0.76).

LC-MS (method 1): R, =0.27 min; MS (ESIpos): m/z=209[M+H]⁺

Intermediate 2-671-(3-{[(2R)-oxolan-2-yl]methoxy}pyridin-4-yl)methanamine

According to the method described for intermediate 2-57 and using3-{[(2R)-oxolan-2-yl]methoxy}pyridine-4-carbonitrile (intermediate 1-67,1.57 g, 7.69 mmol) as a starting material, the title compound wasprepared 1.52 g (95% purity, 90% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.675 (0.81), 1.693 (1.68), 1.713(2.32), 1.721 (2.34), 1.742 (2.49), 1.759 (1.86), 1.803 (2.43), 1.820(3.01), 1.830 (3.53), 1.849 (3.93), 1.867 (4.10), 1.883 (3.45), 1.900(2.47), 1.931 (1.13), 1.949 (0.80), 1.963 (1.45), 1.982 (2.09), 1.994(2.23), 2.011 (2.07), 2.024 (1.52), 2.043 (0.70), 2.327 (0.65), 2.669(0.69), 3.166 (2.08), 3.681 (16.00), 3.696 (5.57), 3.714 (2.28), 3.760(2.02), 3.776 (4.01), 3.795 (3.20), 3.813 (1.26), 4.013 (1.80), 4.028(2.40), 4.038 (3.50), 4.053 (3.90), 4.090 (3.87), 4.099 (4.61), 4.115(2.46), 4.124 (2.70), 4.151 (1.31), 4.168 (2.60), 4.183 (2.73), 4.193(2.20), 7.373 (4.28), 7.384 (4.37), 8.156 (4.90), 8.168 (4.93), 8.234(7.87), 8.271 (0.67).

LC-MS (method 2): R_(t)=0.61 min; MS (ESIpos): m/z=209 [M+H]⁺

Intermediate 2-68 1-{3-[(oxan-2-yl)methoxy]pyridin-4-yl}methanamine

According to the method described for Intermediate 2-57 and using3-[(oxan-2-yl)methoxy]pyridine-4-carbonitrile (intermediate 1-68, 4.44g, 20.3 mmol) as a starting material, the title compound was prepared3.53 g (62% purity, 48% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.297 (1.12), 1.307 (0.98), 1.327(2.67), 1.337 (2.14), 1.356 (3.24), 1.365 (2.48), 1.387 (2.48), 1.396(1.71), 1.424 (2.14), 1.434 (2.83), 1.444 (2.39), 1.457 (3.78), 1.481(10.83), 1.489 (10.17), 1.501 (5.95), 1.522 (2.21), 1.532 (2.67), 1.541(1.66), 1.552 (0.91), 1.561 (1.07), 1.572 (0.87), 1.643 (3.51), 1.674(3.10), 1.810 (5.45), 1.832 (3.99), 2.322 (0.96), 2.327 (1.30), 2.331(0.98), 2.665 (1.03), 2.669 (1.39), 2.673 (1.05), 3.160 (0.66), 3.171(0.71), 3.214 (0.55), 3.234 (0.59), 3.242 (0.55), 3.255 (0.59), 3.269(0.59), 3.359 (3.33), 3.367 (3.28), 3.387 (3.65), 3.395 (4.42), 3.413(2.32), 3.422 (2.51), 3.604 (1.34), 3.609 (1.53), 3.616 (2.62), 3.621(2.87), 3.633 (2.74), 3.643 (3.19), 3.648 (3.33), 3.656 (2.92), 3.677(13.49), 3.773 (1.00), 3.829 (0.71), 3.880 (4.22), 3.903 (3.30), 3.908(3.67), 4.019 (1.94), 4.034 (16.00), 4.046 (15.70), 4.084 (0.71), 4.099(0.71), 4.130 (0.73), 4.146 (0.64), 4.209 (0.41), 4.257 (2.03), 4.267(1.30), 4.272 (1.32), 4.540 (0.43), 7.364 (5.04), 7.376 (5.29), 7.396(0.93), 7.407 (0.77), 7.766 (0.80), 7.778 (0.80), 8.151 (5.97), 8.163(6.22), 8.179 (1.28), 8.227 (9.25), 8.248 (1.19), 8.268 (1.87), 8.370(0.96), 8.382 (0.91), 8.474 (1.62), 8.710 (1.34).

LC-MS (method 2): R_(t)=0.71 min; MS (ESIpos): m/z=223 [M+H]⁺

Intermediate 2-80 tert-butyl(2S)-2-({[4-(aminomethyl)pyridin-3-yl]oxy}methyl)pyrrolidine-1-carboxylate

According to the method described for intermediate 2-57 and usingtert-butyl(2S)-2-{[(4-cyanopyridin-3-yl)oxy]methyl}pyrrolidine-1-carboxylate(Intermediate 1-80, 5.00 g, 16.5 mmol) as a starting material, the titlecompound was prepared 5.05 g (100% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.145 (0.40), 1.380 (13.73), 1.387(11.86), 1.396 (16.00), 1.817 (0.94), 1.921 (1.30), 1.928 (1.57), 1.936(1.50), 1.942 (1.57), 1.956 (1.64), 2.336 (0.77), 2.518 (8.18), 2.523(5.61), 2.678 (0.63), 3.159 (3.17), 3.172 (3.31), 3.296 (2.77), 3.381(0.47), 3.696 (6.08), 4.037 (1.27), 4.054 (1.64), 4.096 (0.87), 4.110(0.77), 4.123 (0.57), 4.135 (0.94), 4.144 (1.14), 4.157 (1.40), 4.166(1.17), 4.420 (0.57), 4.440 (0.57), 4.443 (0.53), 4.462 (0.43), 7.396(1.40), 8.172 (1.74), 8.182 (1.70), 8.274 (2.87).

LC-MS (method 2): R, =0.85 min; MS (ESIpos): m/z=308 M+H]⁺

Intermediate 2-811-{3-[2-(morpholin-4-yl)ethoxy]pyridin-4-yl}methanamine

To a solution of 3-[2-(morpholin-4-yl)ethoxy]pyridine-4-carbonitrile,(intermediate 1-81; 690 mg 2.96 mmol), in methanol, 45.0 mL, was addedpalladium on carbon (10% wt) under a nitrogen atmosphere. After stirringat room temperature for 2 days under an atmosphere of hydrogen, thesuspension was filtered through a pad of celite, washed with methanoland the filtrate was concentrated in vacuo to give1-{3-[2-(morpholin-4-yl)ethoxy]pyridin-4-yl}methanamine, 687 mg (99%).

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=2.43-2.49 (m, 4H), 2.71 (t, 2H),3.52-3.61 (m, 4H), 3.71 (s, 2H), 4.22 (t, 2H), 7.37 (d, 1H), 8.17 (d,1H), 8.27 (s, 1H); UPLC-MS (method 4): R, =0.37 min., 75%. MS (ESIpos):m/z=(M+H)+250.

Intermediate 2-82 1-{3-[(oxan-4-yl)methoxy]pyridin-4-yl}methanamine

To a solution of 3-[(oxan-4-yl)methoxy]pyridine-4-carbonitrile (500 mg,2.29 mmol) in methanol (30 mL) was added 10% Pd/C (97.5 mg, 916 μmol)under a nitrogen atmosphere as a toluene (83 μl) slurry. After stirringat room temperature for 2 days under an atmosphere of hydrogen, thesuspension was filtered through a pad of celite and washed with ethanol.The filtrate was concentrated under reduced pressure to give the desiredtitle compound (490 mg, 96% yield).

¹H NMR (400 MHz, CDCl₃): δ [ppm]=1.41-1.59 (m, 2H), 1.71-1.82 (m, 2H),2.06-2.23 (m, 1H), 3.36-3.56 (m, 4H), 3.88 (s, 2H), 3.97 (d, 2H),4.00-4.11 (m, 2H), 7.26 (d, 1H), 8.21 (s, 1H), 8.25 (d, 1H).

UPLC-MS (method 4): Rt=0.44 min., 68%. MS (ESIpos): m/z=(M+H)+223.

Intermediate 2-96 tert-butyl(2-{[4-(aminomethyl)pyridin-3-yl]oxy}ethyl)methylcarbamate

According to the method described for intermediate 2-57 and usingtert-butyl {2-[(4-cyanopyridin-3-yl)oxy]ethyl}methylcarbamate(intermediate 1-96, 19.1 g, 68.9 mmol) as a starting material, the titlecompound was prepared 18.72 g (90% purity, 97% yield).

LC-MS (method 2): R, =0.84 min; MS (ESIpos): m/z=282 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.233 (0.76), 1.349 (16.00), 1.398(9.05), 1.889 (0.77), 2.518 (2.35), 2.523 (1.57), 2.739 (0.66), 2.863(4.11), 2.888 (3.51), 3.558 (2.60), 3.571 (5.32), 3.585 (2.84), 3.678(3.07), 4.198 (1.79), 4.212 (1.58), 7.394 (1.11), 8.169 (1.53), 8.180(1.54), 8.255 (1.29).

Syntheses of Intermediate 3 Compounds Intermediate 3-11-(difluoromethoxy)-2-isothiocyanatobenzene

To a ice-cooled biphasic system of 2-(difluoromethoxy)aniline (25.0 g,157 mmol) in DCM (20 ml) and sat. NaHCO₃ (20 ml) was added slowlydropwise thiophosgene (13 ml, 160 mmol). The reaction was stirred at 0°C. for 2 h. TLC (EtOAc:Hexane) showed complete conversion. The DCM layerwas separated and washed with sat. NaHCO₃, brine, filtered through ahydrophobic filter and concentrated to give the title compound (29.95 g,95%) which was used directly in the next step.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.09-7.64 (m, 1H).

Intermediate 3-2-1 3-(2-nitrophenyl)propan-1-ol

Into a 10-L 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of3-(2-nitrophenyl)propanoic acid (300 g, 1.54 mol, 1.00 equiv) intetrahydrofuran (1500 mL). This was followed by the addition of BH₃-THF(3315 mL, 2.00 equiv, 1 M) dropwise with stirring at 0° C. in 60 min.The resulting solution was stirred overnight at room temperature. Theresulting solution was extracted with 3×2 L of ethyl acetate and theorganic layers combined. The resulting mixture was washed with 3×1 L ofbrine. The mixture was dried over anhydrous sodium sulfate andconcentrated under vacuum. This resulted in 300 g of3-(2-nitrophenyl)propan-1-ol as yellow oil.

Intermediate 3-2-2 2-(2-nitrophenyl)acetaldehyde

Into a 500-L 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of2-(2-nitrophenyl)ethan-1-ol (300 g, 1.79 mol, 1.00 equiv) indichloromethane (3000 mL), Dess-Martin (837.8 g, 1.10 equiv). Theresulting solution was stirred overnight at room temperature. Thereaction was then quenched by the addition of 2 L of water/ice. The pHvalue of the solution was adjusted to 8 with sodium carbonate. Theresulting solution was extracted with 3×2 L of dichloromethane and theorganic layers combined. The resulting mixture was washed with 3×1 L ofsodium chloride. The mixture was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:1). This resulted in 150 g(51%) of 2-(2-nitrophenyl)acetaldehyde as yellow oil.

Intermediate 3-2-3 1-(2,2-difluoroethyl)-2-nitrobenzene

Into a 5-L 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of2-(2-nitrophenyl)acetaldehyde (150 g, 908.29 mmol, 1.00 equiv) indichloromethane (2000 mL). This was followed by the addition of DAST(366 g, 2.50 equiv) dropwise with stirring at −30° C. in 20 min. Theresulting solution was stirred overnight at room temperature. Thereaction was then quenched by the addition of 300 ml. of methanol. ThepH value of the solution was adjusted to 7 with sodium carbonate. Theresulting solution was extracted with 3×1 L of dichloromethane and theorganic layers combined. The resulting mixture was washed with 3×1 L ofbrine. The mixture was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:10). This resulted in 35 g(21%) of 1-(2,2-difluoroethyl)-2-nitrobenzene as yellow oil.

Intermediate 3-2-4 2-(2,2-difluoroethyl)aniline; oxalic acid salt

Into a 1000-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of1-(2,2-difluoroethyl)-2-nitrobenzene (35 g, 187.02 mmol, 1.00 equiv) inmethanol (350 mL), Palladium carbon (20 g). To the above hydrogen(enough, gas) was introduced in. The resulting solution was stirredovernight at room temperature. The solids were filtered out. Theresulting mixture was concentrated under vacuum. The resulting solutionwas diluted with 300 ml. of EtOAc. This was followed by the addition ofoxalic acid (16 g, 0.95 equiv) in several batches. The resultingsolution was stirred for 30 min at room temperature. The solids werecollected by filtration. This resulted in 33.8 g (73%) of2-(2,2-difluoroethyl)aniline; oxalic acid as an off-white solid.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=2.92-3.12 (2H, m), 5.94-6.35 (1H, m),6.50-6.55 (1H, m), 6.64-6.67 (1H, m), 6.95-6.99 (2H, m).

Intermediate 3-2 2-(2,2-difluoroethyl)aniline; oxalic acid salt

Into a 500-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of2-(2,2-difluoroethyl)aniline (18 g, 114.53 mmol, 1.00 equiv) indichloromethane (180 mL), CaCO₃ (35.5 g, 3.10 equiv), water (180 mL).This was followed by the addition of CsCl₂ (18.3 g, 1.40 equiv) dropwisewith stirring at 0° C. in 30 min. The resulting solution was stirredovernight at room temperature. The reaction was then quenched by theaddition of 1000 ml. of water/ice. The solids were filtered out. Theresulting solution was extracted with 2×500 ml. of dichloromethane andthe organic layers combined. The resulting mixture was washed with 1×500ml. of brine. The mixture was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:20). This resulted in 10.5g (46%) of 1-(2,2-difluoroethyl)-2-isothiocyanatobenzene as yellow oil.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=3.21-3.33 (2H, m), 5.81-6.21 (1H, m),7.23-7.36 (4H, m).

Intermediate 3-3 1-fluoro-3-isothiocyanato-2-methoxybenzene

Using an analogous method as described for Intermediate3-1,3-fluoro-2-methoxyaniline (5.00 g, 35.4 mmol) as the startingmaterial, the title compound was prepared 6.24 g (96% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.32 (m, 1H), 7.10-7.19 (m, 2H), 3.96(d, 3H).

Intermediate 3-4 2-(difluoromethoxy)-1-fluoro-3-isothiocyanatobenzene

Using an analogous method as described for Intermediate3-1,2-(difluoromethoxy)-3-fluoroaniline (5.00 g, 28.2 mmol—Apollo) asthe starting material, the title compound was prepared 5.96 g (96%yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.30-7.49 (m, 4H).

Intermediate 3-5 1-fluoro-3-isothiocyanato-2-methylbenzene

Using an analogous method as described for Intermediate3-1,3-fluoro-2-methylaniline (5.00 g, 40.0 mmol) as the startingmaterial, the title compound was prepared 6.42 g (96% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.19-7.34 (m, 3H), 2.25 (d, 3H).

Intermediate 3-5-1 2-(2-fluoro-6-nitrophenyl)ethan-1-ol

Into a 2000-mL 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of1-fluoro-2-methyl-3-nitrobenzene (400 g, 2.58 mol, 1.00 equiv) in DMSO(1000 mL), Potassium tert-butoxide (46.3 g, 0.16 equiv),polyoxymethylene (77.3 g, 1.00 equiv). The resulting solution wasstirred for 1 h at 70° C. in an oil bath. The reaction mixture wascooled with a water bath. The pH value of the solution was adjusted to 7with hydrogen chloride (12 mol/L). The resulting solution was dilutedwith 1000 ml. of H₂O. The resulting solution was extracted with 4×500ml. of ethyl acetate and the organic layers combined. The resultingmixture was washed with 2×500 ml. of brine. The mixture was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:10). This resulted in 330 g (69%) of2-(2-fluoro-6-nitrophenyl)ethan-1-ol as yellow oil.

Intermediate 3-6-2 2-(2-fluoro-6-nitrophenyl)acetaldehyde

Into a 5000-mL 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of2-(2-fluoro-6-nitrophenyl)ethan-1-ol (330 g, 1.78 mol, 1.00 equiv) indichloromethane (3500 mL), Dess-Martin reagent (794 g, 1.05 equiv). Theresulting solution was stirred overnight at room temperature. Thereaction was then quenched by the addition of 5 L of saturated aqueoussodium carbonate. The resulting solution was extracted with 2×3 L ofdichloromethane and the organic layers combined. The resulting mixturewas washed with 2×2 L of brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:3). Thisresulted in 180 g (55%) of 2-(2-fluoro-6-nitrophenyl)acetaldehyde asyellow oil.

Intermediate 3-6-3 2-(2,2-difluoroethyl)-1-fluoro-3-nitrobenzene

Into a 5000-mL 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of2-(2-fluoro-6-nitrophenyl)acetaldehyde (180 g, 982.87 mmol, 1.00 equiv)in dichloromethane (2500 mL). This was followed by the addition of DAST(405 g) dropwise with stirring at −30° C. in 30 min. The resultingsolution was stirred overnight at room temperature. The reaction mixturewas cooled to −30° C. The reaction was then quenched by the addition of300 mL of methanol. The pH value of the solution was adjusted to 8 withsaturated aqueous sodium carbonate. The resulting solution was extractedwith 3×2 L of dichloromethane and the organic layers combined. Theresulting mixture was washed with 3×2 L of brine. The mixture was driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(1:10). This resulted in 34 g (17%) of2-(2,2-difluoroethyl)-1-fluoro-3-nitrobenzene as yellow oil.

Intermediate 3-6-4 2-(2,2-difluoroethyl)-3-fluoroaniline; oxalic acidsalt

Into a 1000-mL 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of2-(2,2-difluoroethyl)-1-fluoro-3-nitrobenzene (34 g, 165.75 mmol, 1.00equiv) in methanol (500 mL), Palladium carbon (17 g). To the abovehydrogen (enough, gas) was introduced in. The resulting solution wasstirred overnight at room temperature. The solids were filtered out. Theresulting mixture was concentrated under vacuum. The resulting solutionwas diluted with 300 ml. of EtOAc. This was followed by the addition ofoxalic acid (16 g, 0.95 equiv) in several batches. The resultingsolution was stirred for 30 min at room temperature. The solids werecollected by filtration. This resulted in 33.2 g (76%) of2-(2,2-difluoroethyl)-3-fluoroaniline; oxalic acid as an off-whitesolid.

¹H-NMR (300 MHz, CDCl3): δ [ppm]=3.04-3.17 (2H, m), 5.89-6.27 (1H, m),6.29-6.35 (1H, m), 6.45-6.48 (1H, m), 6.93-7.00 (1H, m), 9.65 (1H, s).

Intermediate 3-6 1-fluoro-3-isothiocyanato-2-methylbenzene

Into a 500-mL 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of2-(2,2-difluoroethyl)-3-fluoroaniline; oxalic acid (18 g, 67.88 mmol,1.00 equiv) in dichloromethane (180 mL), a solution of CaCO₃ (52 g, 5.10equiv) in water (180 mL). This was followed by the addition of CSCl₂(17.6 g, 15.00 equiv) dropwise with stirring at 0° C. The resultingsolution was stirred overnight at room temperature. The reaction wasthen quenched by the addition of 500 ml. of saturated aqueous sodiumbicarbonate. The solids were filtered out. The resulting solution wasextracted with 3×500 ml. of dichloromethane and the organic layerscombined. The resulting mixture was washed with 2×300 ml. of brine. Themixture was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:20). This resulted in 10.2 g (69%) of2-(2,2-difluoroethyl)-1-fluoro-3-isothiocyanatobenzene as a yellowliquid.

¹H-NMR (300 MHz, CDCl3): δ [ppm]=3.26-3.39 (2H, m), 5.83-6.23 (1H, m),7.02-7.08 (1H, m), 7.14-7.18 (1H, m), 7.25-7.34 (1H, m).

Intermediate 3-7-1 2-fluoro-6-nitrophenyl prop-2-en-1-yl ether

A mixture of 2-fluoro-6-nitrophenol (5.00 g, 31.8 mmol),3-bromoprop-1-ene (3.4 ml, 40 mmol) and K2CO3 (8.80 g, 63.7 mmol) in DMF(50 ml) was heated at 100° C. for 6 h. The reaction mixture was allowedto cool and diluted with EtOAc (400 ml) and washed with water (3×50 ml),sat. NaCl(aq) and filtered through a hydrophobic filter and concentratedto give the titled compound (5.47 g, 83% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.76 (d, 1H), 7.65-7.71 (m, 1H), 7.34(m, 1H), 5.95-6.05 (m, 1H), 5.38 (dq, 1H), 5.28 (dq, 1H), 4.71 (dq, 2H).

Intermediate 3-7-2 3-fluoro-2-(prop-2-en-1-yloxy)aniline

To a mixture of 2-fluoro-6-nitrophenyl prop-2-en-1-yl ether (5.47 g,27.7 mmol) and ZnCl2 (31.3 g, 139 mmol) in EtOH (300 ml) was added TEA(77 ml, 550 mmol). The reaction was heated at 70° C. for 4 h. Thereaction mixture was filtered and the solid washed with EtOAc (500 ml)and the filtrate was concentrated. The residue was purified by silicachromatography (Hexane:EtOAc) to give the titled compound (1.12 g, 23%yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=6.75 (m, 1H), 6.47 (dt, 1H), 6.33 (m,1H), 6.01-6.13 (m, 1H), 5.32 (dq, 1H), 5.20 (ddt, 1H), 5.13 (s, 2H),4.42 (d, 2H).

Intermediate 3-7 2-fluoro-6-isothiocyanatophenyl prop-2-en-1-yl ether

Using an analogous method as described for Intermediate3-1,3-fluoro-2-(prop-2-en-1-yloxy)aniline (1.12 g, 6.70 mmol) as thestarting material, the title compound was prepared 1.29 g (87% yield).

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm]=7.32 (m, 1H), 7.12-7.20 (m, 2H),6.00-6.09 (m, 1H), 5.41 (dq, 1H), 5.30 (dq, 1H), 4.68 (dq, 2H).

Intermediate 3-8-1 2-ethoxy-1-fluoro-3-nitrobenzene

Using an analogous method as described for Intermediate3-12-1,2-fluoro-6-nitrophenol (5.00 g, 31.8 mmol) as the startingmaterial, the title compound was prepared 5.40 g (87% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.75 (d, 1H), 7.65-7.71 (m, 1H), 7.32(m, 1H), 4.23 (qd, 2H), 1.31 (t, 3H).

Intermediate 3-8-2 2-ethoxy-3-fluoroaniline

An autoclave was charged with 2-ethoxy-1-fluoro-3-nitrobenzene (5.40 g,29.2 mmol), and Platinum/Vanadium (1%/2%) on activated charcoal (1.42 g,50% wet) in MeOH (160 ml) and THF (17 ml) was stirred under a hydrogenatmosphere at RT for 2.5 h. For the work-up, the mixture was filteredthrough a pad of celite, eluted with methanol and the combined filtrateswere concentrated under reduced pressure. The residue was used directlyin the next step without further purification (4.13 g, 91% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=6.74 (m, 1H), 6.47 (dt, 1H), 6.32 (m,1H), 5.12 (s, 2H), 3.92 (q, 2H), 1.29 (t, 3H).

Intermediate 3-8 2-ethoxy-1-fluoro-3-isothiocyanatobenzene

Using an analogous method as described for Intermediate3-1,2-ethoxy-3-fluoroaniline (4.13 g, 26.6 mmol) as the startingmaterial, the title compound was prepared 4.61 g (83% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.31 (m, 1H), 7.09-7.18 (m, 2H), 4.20(qd, 2H), 1.36 (t, 3H).

Intermediate 3-9-1 2-(2,2-difluoroethoxy)-1-fluoro-3-nitrobenzene

Using an analogous method as described for Intermediate3-7-1,2-fluoro-6-nitrophenol (2.91 g, 18.5 mmol) as the startingmaterial, the title compound was prepared 4.71 g (98% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.82 (dt, 1H), 7.74 (m, 1H), 7.39 (m,1H), 6.12-6.54 (m, 1H), 4.49 (tm, 2H).

Intermediate 3-9-2 2-(2,2-difluoroethoxy)-3-fluoroaniline

Using an analogous method as described for Intermediate 3-8-2,2-(2,2-difluoroethoxy)-1-fluoro-3-nitrobenzene (4.10 g, 18.5 mmol) asthe starting material, the title compound was prepared 3.95 g(quantitative).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=6.80 (m, 1H), 6.18-6.52 (m, 3H), 5.24(br s, 2H), 4.14 (m, 2H).

Intermediate 3-9 2-(2,2-difluoroethoxy)-1-fluoro-3-isothiocyanatobenzene

Using an analogous method as described for Intermediate 3-9-2,2-(2,2-difluoroethoxy)-3-fluoroaniline (3.95 g, 20.7 mmol) as thestarting material, the title compound was prepared 3.89 g (77% yield).

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm]=7.35 (m, 1H), 7.15-7.24 (m, 2H), 6.34(brd, 1H), 6.34 (t, 1H), 4.48 (tm, 2H).

Intermediate 3-10 1,2-difluoro-4-isothiocyanato-3-methoxybenzene

Using an analogous method as described for Intermediate3-1,3,4-difluoro-2-methoxyaniline (5.00 g, 31.4 mmol) as the startingmaterial, the title compound was prepared 6.18 g (93% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.18-7.26 (m, 2H), 4.04 (d, 3H).

Intermediate 3-11 1,5-difluoro-3-isothiocyanato-2-methoxybenzene

Using an analogous method as described for Intermediate3-1,3,5-difluoro-2-methoxyaniline (5.00 g, 31.4 mmol) as the startingmaterial, the title compound was prepared 6.18 g (89% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.44 (m, 1H), 7.18-7.23 (m, 1H), 3.92(d, 3H).

Intermediate 3-32 1-chloro-3-isothiocyanato-2-methoxybenzene

According to the method described for intermediate 3-1 and using3-chloro-2-methoxyaniline (4.2 ml, 32 mmol) as a starting material, thetitle compound was prepared 6.58 g (99% purity, 103% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (1.69), 2.522 (1.08), 3.380(11.66), 3.701 (0.51), 3.908 (0.45), 4.067 (0.47), 7.179 (6.92), 7.199(16.00), 7.219 (9.82), 7.337 (9.53), 7.341 (10.67), 7.357 (7.25), 7.361(7.55), 7.498 (8.95), 7.502 (9.32), 7.518 (8.68), 7.522 (8.33).

LC-MS (method 2): R_(t)=1.31 min; MS (ESIpos): m/z=200 [M+H]⁺

Intermediate 3-35 2-ethyl-1-fluoro-3-isothiocyanatobenzene

According to the method described for intermediate 3-1 and using2-ethyl-3-fluoroaniline (2.50 g, 18.0 mmol) as a starting material, thetitle compound was prepared 3.00 g (90% purity, 83% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.108 (7.13), 1.127 (16.00), 1.146(7.13), 2.462 (0.95), 2.483 (1.27), 2.517 (0.79), 2.522 (0.48), 2.637(0.95), 2.641 (1.11), 2.655 (3.17), 2.659 (3.17), 2.674 (3.17), 2.678(3.17), 2.693 (0.95), 2.697 (0.95), 3.461 (0.48), 3.477 (0.63), 3.484(0.63), 3.506 (1.11), 3.528 (2.06), 3.537 (2.69), 3.625 (3.01), 3.648(1.11), 3.663 (0.63), 3.669 (0.63), 7.185 (1.11), 7.189 (1.11), 7.205(1.58), 7.209 (2.53), 7.212 (1.27), 7.229 (1.43), 7.233 (1.74), 7.243(1.27), 7.246 (1.43), 7.263 (3.80), 7.266 (2.38), 7.282 (2.53), 7.296(2.38), 7.301 (2.38), 7.317 (2.53), 7.322 (0.79), 7.337 (0.79).

LC-MS (method 2): R_(t)=1.46 min; MS (ESIpos): m/z=226 [M+H]⁺

Intermediate 3-38 1-chloro-2-(difluoromethoxy)-3-isothiocyanatobenzene

According to the method described for intermediate 3-1 and using3-chloro-2-(difluoromethoxy)aniline (2.00 g, 95% purity, 9.81 mmol) as astarting material, the title compound was prepared 2.40 g (80% purity,83% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.912 (0.72), 2.326 (0.43), 2.517(1.73), 2.522 (1.15), 3.158 (0.58), 3.396 (0.43), 3.418 (0.58), 3.715(0.72), 6.639 (1.30), 6.643 (1.44), 6.659 (1.59), 6.663 (1.59), 6.690(1.44), 6.713 (1.30), 6.717 (1.30), 6.734 (1.73), 6.737 (1.44), 6.876(2.74), 6.934 (0.72), 6.947 (1.87), 6.967 (2.45), 6.987 (1.15), 7.030(7.21), 7.060 (1.30), 7.211 (15.14), 7.327 (0.43), 7.347 (1.01), 7.367(7.50), 7.388 (16.00), 7.391 (8.22), 7.409 (11.39), 7.488 (0.72), 7.494(9.80), 7.497 (10.52), 7.508 (0.86), 7.514 (7.35), 7.518 (6.63), 7.597(10.09), 7.601 (9.80), 7.618 (8.79), 7.622 (7.78), 9.798 (0.58).

LC-MS (method 2): R_(t)=1.31 min; MS (ESIpos): m/z=236 [M+H]⁺

Intermediate 3-39 1-chloro-3-isothiocyanato-2-methoxybenzene

According to the method described for intermediate 3-1 and using3-chloro-2-methoxyaniline (8.4 ml, 63 mmol) as a starting material, thetitle compound was prepared 12.97 g (95% purity, 100% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (1.79), 2.523 (1.10), 3.395(8.24), 3.701 (0.51), 4.067 (0.50), 7.179 (7.00), 7.200 (16.00), 7.220(9.88), 7.338 (9.39), 7.341 (10.13), 7.358 (7.31), 7.362 (7.40), 7.498(8.97), 7.502 (9.26), 7.519 (8.57), 7.523 (7.92).

Intermediate 3-40 1,5-difluoro-3-isothiocyanato-2-methylbenzene

According to the method described for Intermediate 3-38 and using3,5-difluoro-2-methylaniline hydrogen chloride (1/1) (3.13 g, 17.4 mmol)as a starting material, the title compound was prepared 3.10 g (95%purity, 91% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.197 (13.69), 2.199 (16.00), 2.204(13.66), 2.518 (0.46), 7.287 (1.15), 7.294 (2.26), 7.302 (1.13), 7.308(5.47), 7.314 (4.39), 7.325 (1.21), 7.331 (5.10), 7.337 (3.84), 7.343(0.92).

Intermediate 3-41 1-fluoro-3-isothiocyanato-2-(trifluoromethyl)benzene

According to the method described for intermediate 3-1 and using3-fluoro-2-(trifluoromethyl)aniline (1.00 g, 5.58 mmol) as a startingmaterial, the title compound was prepared 1.35 g (75% purity, 82%yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.231 (0.73), 2.331 (1.42), 2.518(7.57), 2.523 (4.91), 5.933 (1.83), 6.385 (2.00), 6.405 (2.21), 6.415(2.04), 6.435 (2.07), 6.609 (3.59), 6.611 (3.42), 6.630 (3.84), 6.632(3.80), 7.202 (1.38), 7.224 (2.66), 7.240 (2.70), 7.260 (1.28), 7.488(5.74), 7.491 (7.57), 7.493 (5.84), 7.510 (6.98), 7.512 (9.54), 7.514(8.78), 7.517 (7.81), 7.519 (8.43), 7.538 (6.67), 7.540 (9.23), 7.542(6.53), 7.599 (12.89), 7.600 (12.86), 7.619 (16.00), 7.621 (15.55),7.779 (6.32), 7.781 (5.94), 7.794 (6.70), 7.795 (6.81), 7.800 (10.40),7.815 (10.30), 7.821 (5.32), 7.835 (4.60), 7.837 (4.39).

LC-MS (method 2): R, =1.40 min; MS (ESIpos): m/z=222 [M+H]⁺

Intermediate 3-42 1-isothiocyanato-2-(trifluoromethyl)benzene

According to the method described for intermediate 3-1 and using2-(trifluoromethyl)aniline (4.6 ml, 97% purity, 36 mmol) as a startingmaterial, the title compound was prepared 6.80 g (60% purity, 57%yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (1.74), 2.523 (1.08), 5.017(3.83), 6.605 (0.97), 6.623 (1.74), 6.625 (1.80), 6.641 (0.80), 6.642(1.10), 6.829 (1.95), 6.850 (2.10), 7.248 (0.87), 7.250 (0.98), 7.252(0.88), 7.268 (1.62), 7.287 (0.81), 7.289 (0.92), 7.290 (0.91), 7.301(1.85), 7.305 (1.74), 7.314 (0.74), 7.321 (1.82), 7.324 (1.69), 7.553(3.39), 7.554 (4.45), 7.556 (4.89), 7.559 (3.66), 7.572 (9.30), 7.574(10.37), 7.576 (9.50), 7.591 (4.79), 7.594 (6.18), 7.596 (4.97), 7.636(0.53), 7.655 (0.54), 7.668 (0.40), 7.683 (0.90), 7.700 (0.87), 7.724(4.80), 7.727 (5.42), 7.744 (16.00), 7.748 (13.39), 7.758 (9.49), 7.760(10.01), 7.777 (8.71), 7.778 (9.85), 7.796 (3.72), 7.798 (3.85), 7.817(0.60), 7.834 (11.34), 7.837 (10.84), 7.853 (9.62), 7.856 (9.30), 8.758(0.89), 9.729 (0.40).

Intermediate 3-44 2-chloro-1-fluoro-4-isothiocyanato-3-methoxybenzene

According to the method described for intermediate 3-1 and using3-chloro-4-fluoro-2-methoxyaniline (4.59 g, 26.1 mmol) as a startingmaterial, the title compound was prepared 5.42 g (95% purity, 91%yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.934 (16.00), 7.287 (1.04), 7.309(1.91), 7.331 (1.55), 7.423 (1.37), 7.437 (1.54), 7.445 (0.99), 7.460(1.12).

Intermediate 3-78 2-bromo-1-chloro-3-isothiocyanatobenzene

According to the method described for intermediate 3-1 and using2-bromo-3-chloroaniline (5.00 g, 24.2 mmol) as a starting material, thetitle compound was prepared 6.08 g (99% purity, 100% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (1.86), 2.522 (1.27), 7.443(6.36), 7.463 (16.00), 7.483 (12.28), 7.530 (9.89), 7.533 (12.44), 7.550(6.35), 7.554 (6.25), 7.616 (10.66), 7.620 (9.74), 7.636 (7.63), 7.640(7.42).

LC-MS (method 2): R_(t)=1.51 min; MS (ESIpos): m/z=249 [M+H]⁺

Syntheses of Intermediate 4 Compounds Intermediate 4-1 tert-butyl5-[(3,5-difluorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

To an ice-cooled solution of tert-butyl2,4-dioxopiperidine-1-carboxylate (5.93 g, 27.8 mmol) and1,3-difluoro-5-isothiocyanatobenzene (4.76 g, 27.8 mmol) in MeCN (40 ml)was added dropwise DBU (6.2 ml, 42 mmol). The reaction mixturesolidified and was sonicated to allow stirring. The reaction was stirredat 0° C. for 16 h. The reaction mixture was added to ice-water (200 ml.)containing cone. HCl (5 mL). The resulting solid was collected byfiltration, washed with water and dried in vacuo at 60° C. for 5 h togive the titled compound 10.4 g (97% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.68 (br s, 1H), 12.53 (br s, 1H),7.64 (brd, 2H), 7.14-7.31 (m, 1H), 3.75 (brt, 2H), 2.74 (brt, 2H), 1.46(s, 9H).

Intermediate 4-2 tert-butyl5-{[2-(difluoromethoxy)phenyl]carbamothioyl}-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

To an ice-cooled mixture of tert-butyl 2,4-dioxopiperidine-1-carboxylate(10.6 g, 49.7 mmol) and 1-(difluoromethoxy)-2-isothiocyanatobenzene(Intermediate 3-1, 10.0 g, 49.7 mmol) in MeCN (100 ml) was added DBU (11ml, 75 mmol) slowly. The reaction was stirred at 0° C. for 16 h. Thereaction mixture was concentrated to ½ volume and the reaction mixtureadded to 1M HCl (500 ml) and extracted with EtOAc. The organics werecombined and concentrated in vacuo. The residue was purified by silicachromatography (EtOAc:Hexane), to give the title compound 16.4 g (80%yield).

¹H-NMR (400 MHz, DMSO-d6): Shift [ppm]=13.32 (br s, 1H), 7.67 (d, 1H),6.99-7.47 (m, 4H), 3.75-3.77 (m, 1H), 3.72-3.88 (m, 1H), 2.89 (br t,2H), 1.48 (s, 9H).

Intermediate 4-3 tert-butyl5-[(2-bromo-3-fluorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

Using an analogous method as described for Intermediate 4-1, 2tert-butyl 2,4-dioxopiperidine-1-carboxylate (5.12 g, 24.0 mmol) and2-bromo-1-fluoro-3-isothiocyanatobenzene (5.57 g, 24.0 mmol—EllanovaLaboratories) as the starting materials, the title compound was prepared10.3 g (87% yield).

Intermediate 4-4 tert-butyl4-hydroxy-5-[(2-methoxyphenyl)carbamothioyl]-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

Using an analogous method as described for Intermediate 4-1, 2tert-butyl 2,4-dioxopiperidine-1-carboxylate (1.81 g, 8.47 mmol) and1-isothiocyanato-2-methoxybenzene (1.40 g, 8.47 mmol) as the startingmaterials, the title compound was prepared 952 mg (28% yield) aftersilica chromatography (Hexane:EtOAc).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.33 (brs, 1H), 7.69 (brd, 1H), 7.32(t, 1H), 7.15 (d, 1H), 7.00 (t, 1H), 3.75-3.85 (m, 5H), 2.87 (br t, 2H),1.48 (s, 9H).

Intermediate 4-5 tert-butyl4-hydroxy-6-oxo-5-{[2-(trifluoromethoxy)phenyl]carbamothioyl}-3,6-dihydropyridine-1(2H)-carboxylate

Using an analogous method as described for Intermediate 4-1, 2tert-butyl 2,4-dioxopiperidine-1-carboxylate (920 mg, 4.32 mmol) and2-isothiocyanatophenyl trifluoromethyl ether (946 mg, 4.32 mmol) as thestarting materials, the title compound was prepared 1.09 g (56% yield)after silica chromatography (Hexane:EtOAc).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=16.42 (br s, 1H), 13.50 (br s, 1H),7.76-7.83 (m, 1H), 7.44-7.55 (m, 3H), 3.78 (t, 2H), 2.90 (t, 2H),1.46-1.54 (m, 9H).

Intermediate 4-6 tert-butyl5-{[2-(2,2-difluoroethyl)phenyl]carbamothioyl}-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

Using an analogous method as described for Intermediate 4-1, 2tert-butyl 2,4-dioxopiperidine-1-carboxylate (2.14 g, 10.0 mmol) and1-(2,2-difluoroethyl)-2-isothiocyanatobenzene (2.00 g, 10.0 mmol) as thestarting materials, the title compound was prepared 3.78 g (87% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=15.43 (br s, 1H), 12.70 (br s, 1H),7.34-7.47 (m, 3H), 7.26 (m, 1H), 6.23 (tt, 1H), 3.78 (t, 2H), 3.13 (m,2H), 2.83 (t, 2H), 1.47 (s, 9H).

Intermediate 4-7 tert-butyl5-[(3-fluoro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

Using an analogous method as described for Intermediate 4-1, 2tert-butyl 2,4-dioxopiperidine-1-carboxylate (7.26 g, 34.1 mmol) and1-fluoro-3-isothiocyanato-2-methoxybenzene (6.24 g, 34.1 mmol) as thestarting materials, the title compound was prepared 9.49 g (67% yield)after slurring the product in MeOH and filtering the solid and drying invacuo.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.37 (br s, 1H), 7.58 (br d, 1H),7.23-7.30 (m, 1H), 7.09-7.20 (m, 1H), 3.84-3.88 (m, 3H), 3.78 (t, 2H),3.17 (s, 3H), 2.88 (br t, 2H), 1.42-1.51 (m, 9H).

Intermediate 4-8 tert-butyl5-{[2-(difluoromethoxy)-3-fluorophenyl]carbamothioyl}-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

Using an analogous method as described for Intermediate 4-1, 2tert-butyl 2,4-dioxopiperidine-1-carboxylate (5.80 g, 27.2 mmol) and2-(difluoromethoxy)-1-fluoro-3-isothiocyanatobenzene (5.96 g, 27.2 mmol)as the starting materials, the title compound was prepared 10.7 g (82%yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.95-13.73 (m, 1H), 7.52 (br s, 1H),7.36-7.48 (m, 2H), 6.87-7.32 (m, 1H), 3.76 (br t, 2H), 2.85 (br s, 2H),1.42-1.51 (m, 9H).

Intermediate 4-9 tert-butyl5-[(3-fluoro-2-methylphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

Using an analogous method as described for Intermediate 4-1, 2tert-butyl 2,4-dioxopiperidine-1-carboxylate (8.19 g, 38.4 mmol) and1-fluoro-3-isothiocyanato-2-methylbenzene (6.42 g, 38.4 mmol)) as thestarting materials, the title compound was prepared 11.1 g (72% yield)after slurring the product in MeOH and filtering the solid and drying invacuo.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=15.81 (br s, 1H), 12.78 (br s, 1H),7.27-7.34 (m, 1H), 7.19 (t, 1H), 7.08 (d, 1H), 3.78 (t, 2H), 2.85 (t,2H), 2.07-2.11 (m, 3H), 1.48 (s, 9H).

Intermediate 4-10 tert-butyl5-{[2-(2,2-difluoroethyl)-3-fluorophenyl]carbamothioyl}-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

Using an analogous method as described for Intermediate 4-1, 2tert-butyl 2,4-dioxopiperidine-1-carboxylate (7.85 g, 36.8 mmol) and2-(2,2-difluoroethyl)-1-fluoro-3-isothiocyanatobenzene (8 g, 36.8 mmol)as the starting materials, the title compound was prepared 12.1 g (76%yield) after slurring the product in MeOH and filtering the solid anddrying in vacuo.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=15.12 (br s, 1H), 12.74 (br s, 1H),7.41-7.49 (m, 1H), 7.27 (t, 1H), 7.16 (d, 1H), 6.22 (br t, 1H), 6.21(brt, 1H), 4.10 (br s, 1H), 3.77 (t, 2H), 3.11-3.25 (m, 5H), 2.80 (brt,2H), 1.47 (s, 9H).

Intermediate 4-11 tert-butyl5-{[3-fluoro-2-(prop-2-en-1-yloxy)phenyl]carbamothioyl}-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

Using an analogous method as described for Intermediate 4-1, 2tert-butyl 2,4-dioxopiperidine-1-carboxylate (1.31 g, 6.17 mmol) and2-fluoro-6-isothiocyanatophenyl prop-2-en-1-yl ether (1.29 g, 6.17 mmol)as the starting materials, the title compound was prepared 1.59 g (58%yield) after slurring the product in MeOH and filtering the solid anddrying in vacuo.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.41 (br s, 1H), 7.61 (br d, 1H),7.08-7.29 (m, 2H), 5.99-6.09 (m, 1H), 5.30-5.39 (m, 1H), 5.18-5.25 (m,1H), 4.57 (d, 2H), 3.77 (t, 2H), 2.82-2.93 (m, 2H), 1.44-1.51 (m, 9H).

Intermediate 4-12 tert-butyl5-[(2-ethoxy-3-fluorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

Using an analogous method as described for Intermediate 4-1, 2tert-butyl 2,4-dioxopiperidine-1-carboxylate (4.97 g, 23.3 mmol) and2-ethoxy-1-fluoro-3-isothiocyanatobenzene (4.60 g, 23.3 mmol) as thestarting materials, the title compound was prepared 6.74 g (67% yield)after slurring the product in MeOH and filtering the solid and drying invacuo.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.54 (brs, 1H), 7.73 (d, 1H),7.07-7.28 (m, 2H), 4.05-4.14 (m, 2H), 3.78 (t, 2H), 3.33 (br s, 2H),2.82-2.94 (m, 2H), 1.43-1.51 (m, 9H), 1.31 (t, 3H).

Intermediate 4-13 tert-butyl5-{[2-(2,2-difluoroethoxy)-3-fluorophenyl]carbamothioyl}-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

Using an analogous method as described for Intermediate 4-1, 2tert-butyl 2,4-dioxopiperidine-1-carboxylate (3.56 g, 16.7 mmol) and2-(2,2-difluoroethoxy)-1-fluoro-3-isothiocyanatobenzene (3.89 g, 16.7mmol) as the starting materials, the title compound was prepared 5.48 g(70% yield) after slurring the product in MeOH and filtering the solidand drying in vacuo.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=16.08 (br s, 1H), 13.20 (br s, 1H),7.57 (brd, 1H), 7.12-7.34 (m, 2H), 6.34 (tt, 1H), 4.28-4.46 (m, 2H),3.77 (t, 2H), 2.87 (br t, 2H), 1.42-1.51 (m, 9H).

Intermediate 4-14 tert-butyl5-[(3,4-difluoro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

Using an analogous method as described for Intermediate 4-1, 2tert-butyl 2,4-dioxopiperidine-1-carboxylate (6.55 g, 30.7 mmol) and1,2-difluoro-4-isothiocyanato-3-methoxybenzene (6.18 g, 30.7 mmol) asthe starting materials, the title compound was prepared 9.03 g (67%yield) after slurring the product in MeOH and filtering the solid anddrying in vacuo.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=16.28 (br s, 1H), 13.15 (br s, 1H),7.42-7.48 (m, 1H), 7.20-7.29 (m, 1H), 3.92 (d, 3H), 3.73-3.83 (m, 2H),2.88 (t, 2H), 1.44-1.53 (m, 9H).

Intermediate 4-15 tert-butyl5-[(3,5-difluoro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

Using an analogous method as described for Intermediate 4-1, 2tert-butyl 2,4-dioxopiperidine-1-carboxylate (6.27 g, 29.4 mmol) and1,5-difluoro-3-isothiocyanato-2-methoxybenzene (5.92 g, 29.4 mmol) asthe starting materials, the title compound was prepared 9.50 g (74%yield) after slurring the product in MeOH and filtering the solid anddrying in vacuo.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=16.19 (br s, 1H), 13.49 (br s, 1H),7.69 (brd, 1H), 7.36 (m, 1H), 3.83 (s, 3H), 3.78 (t, 2H), 2.89 (t, 2H),1.48 (s, 9H).

Intermediate 4-34 tert-butyl5-[(2,3-dichlorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

1,2-dichloro-3-isothiocyanatobenzene (5.00 g, 24.5 mmol) and tert-butyl2,4-dioxopiperidine-1-carboxylate (5.22 g, 24.5 mmol) were solubilisedin 55 ml. acetonitrile, 1,8-diazabicyclo(5.4.0)undec-7-en (5.5 ml, 37mmol) was added carefully at 0° C. under argon atmosphere and themixture was stirred overnight at rt. The reaction mixture was dilutedwith hydrogen chloride solution (1N in water) and stirred for 30 min atrt. The resulting solid was filtered off, the filter-cake was washedwith water and dried at 50° C. in vacuo oven overnight to give 9.40 g ofthe title compound (92% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.467 (16.00), 1.484 (0.56), 1.622(0.34), 1.644 (0.25), 1.661 (0.20), 1.674 (0.17), 1.898 (0.19), 1.913(0.31), 1.927 (0.19), 2.075 (0.20), 2.327 (0.18), 2.518 (0.60), 2.523(0.39), 2.621 (0.30), 2.647 (0.32), 2.665 (0.24), 2.669 (0.29), 2.673(0.25), 3.249 (0.25), 3.459 (0.23), 3.473 (0.39), 3.487 (0.22), 3.538(0.28), 3.561 (0.29), 3.727 (0.50), 7.357 (0.17), 7.377 (0.36), 7.383(0.28), 7.397 (0.28), 7.544 (0.27), 7.547 (0.33), 7.560 (0.29), 7.564(0.31), 7.568 (0.25), 7.580 (0.18).

LC-MS (method 2): R, =0.70 min; MS (ESIpos): m/z=416 [M−H]⁻

Intermediate 4-32 tert-butyl5-[(3-chloro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

According to the method described for Intermediate 4-34 and using1-chloro-3-isothiocyanato-2-methoxybenzene (intermediate 3-32, 4.00 g,20.0 mmol) as a starting material, the title compound was prepared(additional flash chromatography) 6.54 g (90% purity, 71% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (1.09), 1.172 (2.39), 1.190(1.20), 1.484 (16.00), 1.496 (0.78), 1.987 (4.14), 2.867 (0.45), 2.883(0.85), 2.900 (0.48), 3.336 (0.71), 3.669 (0.68), 3.774 (8.05), 3.787(1.07), 3.799 (0.50), 3.803 (0.56), 4.017 (0.90), 4.035 (0.89), 7.201(0.52), 7.221 (1.13), 7.241 (0.64), 7.453 (0.62), 7.457 (0.67), 7.474(0.55), 7.478 (0.54), 7.716 (0.46), 7.718 (0.46), 7.736 (0.43), 7.738(0.41).

LC-MS (method 2): R, =1.49 min; MS (ESIpos): m/z=413 [M+H]⁺

Intermediate 4-35 tert-butyl5-[(2-ethyl-3-fluorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

According to the method described for Intermediate 4-34 and using2-ethyl-1-fluoro-3-isothiocyanatobenzene (intermediate 3-35, 3.00 g,16.6 mmol) as a starting material, the title compound was prepared 5.46g (95% purity, 79% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.066 (1.02), 1.085 (2.41), 1.104(1.06), 1.477 (16.00), 1.486 (1.04), 2.074 (0.65), 2.518 (1.12), 2.522(0.92), 2.538 (0.61), 2.858 (0.69), 3.771 (0.55), 3.787 (0.98), 3.803(0.50), 7.092 (0.50), 7.112 (0.55), 7.186 (0.45), 7.311 (0.44), 7.327(0.41).

LC-MS (method 2): R_(t)=0.72 min; MS (ESIpos): m/z=395 [M+H]⁺

Intermediate 4-36 tert-butyl5-[(3-chloro-2-methylphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

According to the method described for intermediate 4-34 and using1-chloro-3-isothiocyanato-2-methylbenzene (CAS: 19241-35-1; 2.50 g, 13.6mmol) as a starting material, the title compound was prepared 4.68 g(90% purity, 78% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.478 (16.00), 2.198 (4.35), 2.832(0.48), 2.848 (0.92), 2.864 (0.51), 3.769 (0.53), 3.785 (0.95), 3.801(0.50), 7.180 (0.46), 7.199 (0.63), 7.283 (0.42), 7.304 (0.76), 7.447(0.62), 7.466 (0.48).

LC-MS (method 2): R_(t)=0.72 min; MS (ESIpos): m/z=397 [M+H]⁺

Intermediate 4-37 tert-butyl5-[(2-bromo-3-fluorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

According to the method described for intermediate 4-34 and using2-bromo-1-fluoro-3-isothiocyanatobenzene (CAS: 364364-00-1, 5.57 g, 24.0mmol) as a starting material, the title compound was prepared 10.3 g(90% purity, 87% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.424 (0.24), 1.474 (16.00), 1.486(0.76), 1.505 (0.17), 1.600 (0.20), 1.621 (0.23), 1.630 (0.22), 1.643(0.19), 1.912 (0.23), 2.518 (0.34), 2.523 (0.23), 2.624 (0.19), 2.650(0.20), 2.779 (0.22), 3.245 (0.19), 3.249 (0.19), 3.459 (0.17), 3.473(0.29), 3.537 (0.20), 3.561 (0.21), 3.737 (0.38), 3.752 (0.61), 3.768(0.35), 7.323 (0.21), 7.426 (0.20), 7.432 (0.25), 7.455 (0.41), 7.472(0.27).

LC-MS (method 1): R, =1.48 min; MS (ESIpos): m/z=446 [M+H]⁺

Intermediate 4-38 tert-butyl5-{[3-chloro-2-(difluoromethoxy)phenyl]carbamothioyl}-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

According to the method described for Intermediate 4-34 and using1-chloro-2-(difluoromethoxy)-3-isothiocyanatobenzene (2.44 g, 94%purity, 9.73 mmol) as a starting material, (additional flashchromatography) the title compound was prepared 2.11 g (82% purity, 38%yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.475 (16.00), 1.486 (2.52), 2.083(3.92), 2.518 (3.00), 2.522 (1.89), 3.749 (0.52), 3.764 (0.85), 3.780(0.52), 7.036 (0.76), 7.411 (0.52), 7.599 (0.44).

LC-MS (method 2): R, =0.75 min; MS (ESIpos): m/z=449 [M+H]⁺

Intermediate 4-39 2 tert-butyl5-[(2-chlorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

According to the method described for Intermediate 4-34 and using1-chloro-2-isothiocyanatobenzene (CAS: 2740-81-0, 6.4 ml, 49 mmol) as astarting material, the title compound was prepared 12.5 g (70% purity,49% yield).

LC-MS (method 2): R_(t)=0.64 min; MS (ESIneg): m/z=381 [M−H]⁻

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.442 (16.00), 1.598 (0.47), 1.608(0.46), 1.618 (0.46), 1.909 (0.59), 2.261 (0.47), 2.275 (0.74), 2.290(0.49), 2.627 (0.42), 2.653 (0.44), 3.246 (0.60), 3.471 (0.66), 3.535(0.46), 3.558 (0.50), 3.582 (0.49), 3.597 (0.72), 3.612 (0.45), 7.072(0.42), 7.076 (0.41), 7.221 (0.40), 7.400 (0.64), 7.404 (0.66), 7.421(0.60), 7.424 (0.55), 8.177 (0.48), 8.181 (0.48), 8.197 (0.47), 8.201(0.44), 14.352 (0.78).

Intermediate 4-40 tert-butyl5-[(3,5-difluoro-2-methylphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

According to the method described for Intermediate 4-34 and using1,5-difluoro-3-isothiocyanato-2-methylbenzene (intermediate 3-40, 3.10g, 16.7 mmol) as a starting material, (additional flash chromatography)the title compound was prepared 5.24 g (95% purity, 75% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.477 (16.00), 2.048 (2.23), 2.074(0.72), 2.518 (0.65), 2.523 (0.41), 2.832 (0.48), 2.848 (0.91), 2.865(0.50), 3.345 (0.39), 3.763 (0.57), 3.779 (1.02), 3.795 (0.52), 7.060(0.30), 7.084 (0.30), 7.234 (0.19), 7.240 (0.20), 7.258 (0.34), 7.264(0.34), 7.282 (0.19), 7.288 (0.19), 12.773 (0.22), 15.600 (0.21).

LC-MS (method 2): R_(t)=0.67 min; MS (ESIpos): m/z=399 [M+H]⁺

Intermediate 4-41 tert-butyl5-{[3-fluoro-2-(trifluoromethyl)phenyl]carbamothioyl}-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

According to the method described for Intermediate 4-34 and using1-fluoro-3-isothiocyanato-2-(trifluoromethyl)benzene (intermediate 3-41,1.35 g, 91% purity, 5.55 mmol) as a starting material, the titlecompound was prepared 1.98 g (95% purity, 78% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.479 (16.00), 2.518 (0.63), 2.895(0.53), 3.769 (0.55), 3.785 (0.98), 3.802 (0.50), 7.287 (0.46), 7.306(0.50).

LC-MS (method 2): R, =0.77 min; MS (ESIpos): m/z=435 [M+H]⁺

Intermediate 4-42 tert-butyl4-hydroxy-6-oxo-5-{[2-(trifluoromethyl)phenyl]carbamothioyl}-3,6-dihydropyridine-1(2H)-carboxylate

According to the method described for Intermediate 4-34 and using1-isothiocyanato-2-(trifluoromethyl)benzene (intermediate 3-42, 6.80 g,33.5 mmol) as a starting material, (additional flash chromatography) thetitle compound was prepared 5.01 g (76% purity, 28% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.477 (16.00), 2.518 (0.45), 2.523(0.30), 2.915 (0.41), 3.779 (0.50), 3.795 (0.91), 3.812 (0.47), 7.570(0.57), 7.589 (0.85), 7.608 (0.24), 7.753 (0.26), 7.772 (0.39), 7.791(0.18), 7.838 (0.44), 7.857 (0.38), 13.585 (0.19).

LC-MS (method 2): R, =0.67 min; MS (ESIneg): m/z=415 [M−H]⁻

Intermediate 4-43 tert-butyl5-{[3,5-difluoro-2-(difluoromethoxy)phenyl]carbamothioyl}-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

To a solution of 1,5-difluoro-3-isothiocyanato-2-difluoromethoxybenzene(30.0 g, 149 mmol, 1.00 eq) in DCM (120 mL) was added DBU (45.4 g, 298mmol, 45.0 mL, 2.00 eq) and compound tert-butyl2,4-dioxopiperidine-1-carboxylate (32.0 g, 150 mmol, 1.01 eq). Themixture was stirred at 15° C. for 12 hrs. The reaction mixture waspoured into 1 M HCl aqueous solution (250 mL) and extracted with DCM(150 mL*3). The combined organic layer was washed with brine (150 mL),dried over Na₂SO₄, filtered and concentrated. The yellow residue waspurified by column chromatography (SiO₂, Petroleum ether: Ethylacetate=10:1-5:1)). The title compound (25.0 g, 60.3 mmol, 40.5% yield)was obtained as yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ [ppm]: 13.45-13.34 (m, 1H), 7.42-7.39 (m, 1H),6.95-6.88 (m, 1H), 4.02-4.01 (m, 3H), 3.88-3.83 (m, 2H), 2.84-2.75 (m,2H), 1.64-1.54 (m, 9H)

Intermediate 4-44 tert-butyl5-[(3-chloro-4-fluoro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

According to the method described for Intermediate 4-34 and using2-chloro-1-fluoro-4-isothiocyanato-3-methoxybenzene (intermediate 3-44,5.42 g, 24.9 mmol) as a starting material, (additional flashchromatography) the title compound was prepared 5.96 g (95% purity, 53%yield).

LC-MS (method 1): R_(t)=1.50 min; MS (ESIpos): m/z=431 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (2.03), 1.172 (4.39), 1.190(2.24), 1.482 (16.00), 1.987 (8.02), 2.518 (0.60), 2.876 (0.74), 2.893(0.41), 3.769 (0.54), 3.785 (0.98), 3.801 (0.56), 3.813 (7.96), 3.999(0.59), 4.017 (1.78), 4.035 (1.76), 4.053 (0.57), 7.280 (0.49), 7.303(0.92), 7.325 (0.54).

Intermediate 4-45 tert-butyl5-[(5-fluoro-2-methylphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

According to the method described for Intermediate 4-34 and using4-fluoro-2-isothiocyanato-1-methylbenzene (CAS: 175205-39-7, 1.00 g,5.98 mmol) as a starting material, the title compound was prepared 2.10g (94% purity, 92% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.478 (16.00), 2.154 (3.37), 2.518(0.39), 2.523 (0.27), 2.840 (0.43), 2.857 (0.83), 2.872 (0.46), 3.765(0.54), 3.781 (0.97), 3.797 (0.50), 7.104 (0.16), 7.111 (0.22), 7.126(0.35), 7.133 (0.48), 7.147 (0.20), 7.154 (0.30), 7.162 (0.32), 7.169(0.27), 7.186 (0.31), 7.193 (0.26), 7.344 (0.34), 7.361 (0.38), 7.365(0.35), 7.381 (0.29), 12.876 (0.21), 15.970 (0.31).

LC-MS (method 2): R, =0.64 min; MS (ESIpos): m/z=381 [M+H]⁺

Intermediate 4-78 tert-butyl5-[(2-bromo-3-chlorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

According to the method described for Intermediate 4-34 and using2-bromo-1-chloro-3-isothiocyanatobenzene (intermediate 3-78, 6.08 g,24.5 mmol) as a starting material, (additional flash chromatography) thetitle compound was prepared 4.04 g (99% purity, 35% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.155 (0.55), 1.172 (1.25), 1.190(0.49), 1.483 (16.00), 1.987 (1.98), 2.518 (0.71), 2.522 (0.48), 2.907(0.67), 3.778 (0.53), 3.794 (0.95), 3.811 (0.49), 4.017 (0.48), 4.034(0.43), 7.431 (0.56), 7.434 (0.55), 7.471 (0.65), 7.491 (1.05), 7.511(0.47), 7.628 (0.58), 7.631 (0.56), 7.648 (0.45), 7.652 (0.42).

LC-MS (method 2): R, =0.71 min; MS (ESIpos): m/z=461 [M+H]⁺

Syntheses of Intermediate 5 Compounds Intermediate 5-1N-(3,5-difluorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

To an-ice-cooled solution of tert-butyl5-[(3,5-difluorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate(Intermediate 4-1; 10.3 g, 26.9 mmol) in DCM (100 ml) was added TFA (10ml). The reaction mixture was stirred at 0° C. for 4 h and concentrated.The residue was redissolved in DCM and washed with sat. NaHCO3, filteredthrough a hydrophobic filter and concentrated to give the titledcompound 6.04 g (79% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=16.33 (s, 1H), 14.45 (br s, 1H),14.29-15.04 (m, 1H), 8.01-9.79 (m, 1H), 7.29 (br s, 2H), 7.18 (br s,1H), 3.22-3.50 (m, 2H), 2.56-2.87 (m, 2H).

Intermediate 5-2N-[2-(difluoromethoxy)phenyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

To an ice-cooled solution of tert-butyl5-{[2-(difluoromethoxy)phenyl]carbamothioyl}-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate(Intermediate 4-2, 16.4 g, 39.6 mmol) in DCM (30 ml) was added TFA (30ml) and stirred for 15 min and allowed to warm to RT. The reactionmixture was poured onto a sat. NaHCO₃ solution and extracted with DCM.The organics were combined and filtered through hydrophobic filter andconcentrated to give the title compound (12.43 g, 95%).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.04-14.82 (m, 1H), 8.05-9.60 (m,1H), 7.74 (t, 1H), 6.88-7.50 (m, 5H), 3.43 (m, 1H), 3.26-3.32 (m, 1H),2.78 (t, 1H), 2.58-2.68 (m, 1H).

Intermediate 5-3N-(2-bromo-3-fluorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 5-2,intermediate 4-3 (10.0 g, 22.5 mmol) as the starting material, the titlecompound was prepared 4.66 g (54% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.03-14.77 (m, 1H), 8.09-9.49 (m,1H), 7.26-7.52 (m, 3H), 3.35-3.48 (m, 1H), 3.23-3.32 (m, 1H), 2.80 (brt,1H), 2.59-2.70 (m, 1H).

Intermediate 5-44-hydroxy-N-(2-methoxyphenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 5-2,intermediate 4-4 (940 mg, 2.48 mmol) as the starting material, the titlecompound was prepared 680 mg (93% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.35 (br s, 1H), 8.05 (br s, 1H),7.72 (br d, 1H), 7.26 (dt, 1H), 7.08-7.16 (m, 1H), 6.92-7.02 (m, 1H),3.80 (s, 3H), 3.37-3.45 (m, 1H), 3.25-3.32 (m, 1H), 2.75 (br t, 1H),2.56-2.68 (m, 1H).

Intermediate 5-54-hydroxy-2-oxo-N-[2-(trifluoromethoxy)phenyl]-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 5-2,intermediate 4-5 (1.02 g, 2.36 mmol) as the starting material, the titlecompound was prepared 785 mg (95% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=16.40 (br d, 1H), 14.20-14.99 (m,1H), 8.10-9.53 (m, 1H), 7.77-7.90 (m, 1H), 7.33-7.53 (m, 3H), 3.35-3.47(m, 1H), 3.26-3.32 (m, 1H), 2.80 (br t, 1H), 2.64 (br t, 1H).

Intermediate 5-6N-[2-(2,2-difluoroethyl)phenyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 5-2,intermediate 4-6 (13.77 g, 9.13 mmol) as the starting material, thetitle compound was prepared 2.79 g (93% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.82-14.53 (m, 1H), 7.93-9.50 (m,1H), 7.25-7.47 (m, 4H), 6.20 (tt, 1H), 3.36-3.48 (m, 1H), 3.28-3.32 (m,1H), 3.08 (m, 2H), 2.78 (br s, 1H), 2.59-2.72 (m, 1H).

Intermediate 5-7N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 5-2,intermediate 4-7 (9.49 g, 23.9 mmol) as the starting material, the titlecompound was prepared 6.98 g (89% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.15-14.78 (m, 1H), 8.04-9.55 (m,1H), 7.65 (t, 1H), 6.99-7.26 (m, 2H), 3.79-3.85 (m, 3H), 3.43 (m, 1H),3.24-3.32 (m, 1H), 2.61-2.81 (m, 2H).

Intermediate 5-8N-[2-(difluoromethoxy)-3-fluorophenyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 5-2,intermediate 4-8 (10.7 g, 24.8 mmol) as the starting material, the titlecompound was prepared 7.38 g (89% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.10-14.82 (m, 1H), 8.06-9.71 (m,1H), 7.57 (br d, 1H), 7.32-7.43 (m, 2H), 6.89-7.31 (m, 1H), 3.35-3.46(m, 1H), 3.26-3.32 (m, 1H), 2.79 (br t, 1H), 2.59-2.68 (m, 1H).

Intermediate 5-9N-(3-fluoro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 5-2,intermediate 4-9(11.1 g, 29.1 mmol) as the starting material, the titlecompound was prepared 7.25 g (84% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.89-14.53 (m, 1H), 7.88-9.66 (m,1H), 7.24-7.33 (m, 1H), 7.11-7.20 (m, 2H), 3.40-3.46 (m, 1H), 3.27-3.33(m, 1H), 2.78 (t, 1H), 2.59-2.68 (m, 1H), 2.06 (s, 3H).

Intermediate 5-10N-[2-(2,2-difluoroethyl)-3-fluorophenyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 5-2,intermediate 4-10 (12.1 g, 28.0 mmol) as the starting material, thetitle compound was prepared 8.81 g (90% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.77-14.57 (m, 1H), 7.98-9.51 (m,1H), 7.38-7.49 (m, 1H), 7.15-7.30 (m, 2H), 6.21 (tt, 1H), 3.35-3.47 (m,1H), 3.26-3.32 (m, 1H), 3.11 (m, 2H), 2.79 (brt, 1H), 2.60-2.69 (m, 1H).

Intermediate 5-11N-[3-fluoro-2-(prop-2-en-1-yloxy)phenyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 5-2,intermediate 4-11 (1.58 g, 3.74 mmol) as the starting material, thetitle compound was prepared 1.17 g (87% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.10-14.77 (m, 1H), 8.06-9.51 (m,1H), 7.62 (br m, 1H), 6.99-7.25 (m, 2H), 5.95-6.17 (m, 1H), 5.18-5.39(m, 2H), 4.51-4.61 (m, 2H), 3.36-3.46 (m, 1H), 3.26-3.32 (m, 1H),2.73-2.84 (m, 1H), 2.58-2.66 (m, 1H).

Intermediate 5-12N-(2-ethoxy-3-fluorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 5-2,intermediate 4-12 (6.97 g, 17.0 mmol) as the starting material, thetitle compound was prepared 5.20 g (94% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.09-14.93 (m, 1H), 8.08-9.65 (m,1H), 7.71 (m, 1H), 6.95-7.24 (m, 2H), 4.00-4.12 (m, 2H), 3.42 (m, 1H),3.26-3.32 (m, 1H), 2.78 (t, 1H), 2.60-2.71 (m, 1H), 1.21-1.32 (m, 3H).

Intermediate 5-13N-[2-(2,2-difluoroethoxy)-3-fluorophenyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 5-2,intermediate 4-13 (5.48 g, 12.3 mmol) as the starting material, thetitle compound was prepared 3.95 g (84% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.07-14.80 (m, 1H), 8.09-9.53 (m,1H), 7.54-7.66 (m, 1H), 7.06-7.31 (m, 2H), 6.07-6.60 (m, 1H), 4.22-4.39(m, 2H), 3.35-3.46 (m, 1H), 3.25-3.32 (m, 1H), 2.79 (brt, 1H), 2.60-2.73(m, 1H).

Intermediate 5-14N-(3,4-difluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 5-2,intermediate 4-14 (9.03 g, 21.8 mmol) as the starting material, thetitle compound was prepared 6.69 g (93% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.92-14.65 (m, 1H), 8.04-9.61 (m,1H), 7.48-7.58 (m, 1H), 7.16-7.27 (m, 1H), 3.89 (s, 2H), 3.82-3.95 (m,1H), 3.39-3.48 (m, 1H), 3.25-3.32 (m, 1H), 2.78 (brt, 1H), 2.63 (brt,1H).

Intermediate 5-15N-(3,5-difluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 5-2,intermediate 4-15 (9.50 g, 22.9 mmol) as the starting material, thetitle compound was prepared 6.99 g (92% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.34-15.11 (m, 1H), 8.11-9.63 (m,1H), 7.81 (br d, 1H), 7.23-7.36 (m, 1H), 3.81 (s, 3H), 3.43 (br t, 1H),3.23-3.33 (m, 1H), 2.80 (br t, 1H), 2.60-2.70 (m, 1H).

Intermediate 5-32N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

To a solution of tert-butyl5-[(3-chloro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate(intermediate 4-32, 6.54 g, 15.8 mmol) in 94 ml. dichloromethane wasadded trifluoroacetic acid (12 ml, 160 mmol) and the mixture was stirred1.5 h at rt. The reaction mixture was concentrated under reducedpressure and the residue was solved in ethyl acetate and washed withsaturated aqueous solution and sodium bicarbonate and brine. The organiclayer was filtered through a waterresistant filter and the filtrate wasdried to dryness. The residue was purified by flash chromatography togive 4.06 g of the title compound (95% purity, 78% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.172 (0.45), 1.987 (0.74), 2.518(1.27), 2.523 (0.87), 2.625 (1.12), 2.643 (2.13), 2.661 (1.30), 2.669(0.53), 2.773 (1.04), 2.791 (2.17), 2.808 (1.17), 3.279 (0.75), 3.286(0.85), 3.297 (1.43), 3.304 (1.46), 3.314 (0.82), 3.411 (0.76), 3.418(0.86), 3.430 (1.37), 3.437 (1.35), 3.447 (0.76), 3.455 (0.67), 3.742(16.00), 3.744 (15.67), 7.154 (0.75), 7.174 (1.70), 7.187 (0.86), 7.194(1.08), 7.207 (1.62), 7.228 (0.90), 7.379 (1.09), 7.382 (1.16), 7.399(0.97), 7.402 (0.97), 7.422 (1.10), 7.425 (1.11), 7.442 (0.92), 7.445(0.87), 7.779 (0.93), 7.798 (0.91), 7.815 (1.08), 7.836 (0.98), 8.184(0.86), 9.368 (0.71), 14.326 (1.64), 14.693 (1.39), 16.447 (3.78),16.457 (3.62).

LC-MS (method 2): R, =1.50 min; MS (ESIpos): m/z=431 [M+H]⁺

Intermediate 5-34N-(2,3-dichlorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for intermediate 5-32 and usingtert-butyl5-[(2,3-dichlorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate(intermediate 4-34, 9.40 g, 22.5 mmol) as the starting material, thetitle compound was prepared 5.71 g (62% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.018 (1.18), 1.050 (1.33), 1.072(0.81), 1.102 (0.59), 1.132 (0.81), 1.154 (1.84), 1.172 (3.17), 1.189(1.84), 1.199 (0.88), 1.231 (1.92), 1.259 (1.40), 1.486 (0.66), 1.593(1.33), 1.626 (1.18), 1.695 (1.25), 1.727 (1.18), 1.907 (2.14), 1.987(5.97), 2.322 (3.17), 2.326 (4.28), 2.331 (3.17), 2.518 (15.85), 2.522(9.44), 2.638 (11.06), 2.664 (7.82), 2.669 (7.52), 2.673 (5.53), 2.798(8.11), 3.436 (9.81), 4.017 (1.18), 4.035 (1.11), 5.560 (1.33), 5.579(1.25), 7.392 (4.42), 7.410 (10.03), 7.430 (9.22), 7.565 (12.24), 7.585(16.00), 7.605 (9.51), 8.134 (0.74), 8.197 (4.35), 9.418 (3.91), 14.273(6.93), 14.665 (6.64), 16.114 (1.03), 16.295 (9.95), 16.352 (5.82),16.503 (1.11).

LC-MS (method 2): R_(t)=0.55 min; MS (ESIpos): m/z=316 [M−H]⁻

Intermediate 5-35N-(2-ethyl-3-fluorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for intermediate 5-32 and usingtert-butyl5-[(2-ethyl-3-fluorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate(intermediate 4-35, 5.46 g, 71% purity, 9.83 mmol) as the startingmaterial, the title compound was prepared 4.00 g (70% purity, 97%yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.052 (6.61), 1.071 (16.00), 1.089(6.75), 1.116 (0.56), 1.224 (4.60), 1.734 (1.58), 2.326 (0.43), 2.472(1.56), 2.518 (2.10), 2.523 (1.69), 2.647 (0.85), 2.659 (0.85), 2.664(0.98), 2.668 (1.03), 2.673 (0.80), 2.782 (0.89), 3.423 (0.82), 4.037(0.62), 7.160 (2.35), 7.288 (0.98), 8.170 (0.48), 14.073 (0.46), 14.414(0.52).

LC-MS (method 2): R_(t)=0.55 min; MS (ESIpos): m/z=295 [M+H]⁺

Intermediate 5-36N-(3-chloro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 5-32 and usingtert-butyl5-[(3-chloro-2-methylphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate(intermediate 4-36, 4.67 g, 11.8 mmol) as the starting material, thetitle compound was prepared 3.54 g (90% purity, 91% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.175 (16.00), 2.298 (0.54), 2.323(0.48), 2.327 (0.70), 2.332 (0.72), 2.518 (3.34), 2.523 (2.06), 2.612(0.74), 2.630 (1.44), 2.649 (0.84), 2.665 (0.56), 2.669 (0.71), 2.673(0.51), 2.762 (0.82), 2.780 (1.64), 2.798 (0.90), 3.288 (0.73), 3.299(1.17), 3.306 (1.19), 3.316 (0.73), 3.429 (1.24), 3.435 (1.17), 3.447(0.69), 7.204 (0.51), 7.225 (1.19), 7.250 (1.77), 7.270 (1.07), 7.276(0.90), 7.297 (1.04), 7.316 (0.40), 7.407 (0.84), 7.431 (1.24), 7.452(0.72), 8.148 (0.76), 9.321 (0.63), 14.011 (1.08), 14.323 (1.03), 16.402(1.62), 16.429 (1.40).

LC-MS (method 2): R_(t)=0.57 min; MS (ESIpos): m/z=297 [M+H]⁺

Intermediate 5-37N-(2-bromo-3-fluorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for intermediate 5-32 and usingtert-butyl5-[(2-bromo-3-fluorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate(intermediate 4-37, 10.0 g, 22.5 mmol) as the starting material, thetitle compound was prepared 3.54 g (90% purity, 91% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.224 (0.94), 1.416 (0.88), 1.446(0.83), 1.456 (2.59), 1.530 (0.59), 1.540 (1.12), 1.625 (0.47), 1.907(0.44), 2.322 (1.50), 2.327 (1.97), 2.332 (1.59), 2.518 (7.96), 2.523(5.22), 2.535 (1.74), 2.551 (1.33), 2.625 (8.90), 2.643 (16.00), 2.661(9.61), 2.786 (7.13), 2.803 (13.17), 2.821 (7.16), 3.296 (7.72), 3.308(11.73), 3.314 (12.61), 3.422 (6.90), 3.429 (7.66), 3.441 (11.29), 3.446(10.84), 3.457 (6.36), 5.757 (3.06), 7.169 (0.50), 7.190 (0.56), 7.283(1.09), 7.309 (4.24), 7.329 (8.69), 7.347 (7.84), 7.366 (8.22), 7.386(12.46), 7.405 (14.14), 7.426 (2.92), 7.436 (5.57), 7.456 (7.25), 7.471(8.34), 7.489 (6.54), 7.504 (4.54), 7.524 (1.56), 7.801 (0.41), 8.017(0.56), 8.038 (0.56), 8.196 (5.95), 9.411 (5.57), 9.748 (0.59), 14.210(11.93), 14.613 (8.99), 16.337 (14.44), 16.388 (11.23).

LC-MS (method 2): R, =1.16 min; MS (ESIpos): m/z=346 [M+H]⁺

Intermediate 5-38N-[3-chloro-2-(difluoromethoxy)phenyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 5-32 and usingtert-butyl5-{[3-chloro-2-(difluoromethoxy)phenyl]carbamothioyl}-6-hydroxy-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate(intermediate 4-38, 1.10 g, 88% purity, 2.16 mmol) as the startingmaterial, the title compound was prepared 989 mg (76% purity, 100%yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.390 (0.59), 2.084 (0.44), 2.331(3.08), 2.336 (1.39), 2.518 (16.00), 2.523 (10.94), 2.541 (0.95), 2.612(2.35), 2.629 (4.40), 2.647 (2.64), 2.673 (3.30), 2.678 (1.54), 2.694(0.44), 2.713 (0.81), 2.730 (0.51), 2.775 (2.06), 2.793 (3.74), 2.810(2.13), 3.300 (3.30), 3.426 (6.09), 3.433 (6.02), 6.825 (1.47), 6.839(1.25), 7.006 (3.08), 7.020 (2.50), 7.115 (0.51), 7.134 (0.73), 7.188(1.54), 7.201 (1.25), 7.296 (0.44), 7.318 (0.81), 7.327 (0.81), 7.335(1.76), 7.357 (1.39), 7.377 (3.01), 7.397 (2.42), 7.409 (2.57), 7.429(1.39), 7.549 (2.50), 7.569 (2.42), 7.585 (2.42), 7.605 (4.26), 7.626(4.33), 7.646 (1.91), 8.132 (0.37), 8.166 (2.06), 8.183 (0.66), 8.192(0.59), 8.202 (0.44), 9.392 (2.13), 12.389 (0.66), 12.678 (0.44), 14.169(3.60), 14.610 (2.72), 16.074 (0.44), 16.326 (4.40), 16.361 (3.30).

LC-MS (method 2): R, =0.57 min; MS (ESIpos): m/z=349 [M+H]⁺

Intermediate 5-39N-(2-chlorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Tert-butyl5-[(2-chlorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate(intermediate 4-39, 12.4 g, 32.4 mmol) was dissolved in a mixture of 250ml. dichloromethane and of 105 ml. methanol, treated with hydrogenchloride (81 ml, 4.0 M in 1,4-dioxane, 320 mmol) and stirred overnightat rt. The reaction mixture was diluted with ice-water and the aqueousphase was extracted with a mixture of dichloromethane/methanol (9:1) twotimes. The combined organic layer was dried over sodium sulfate,filtered and the filtrate was concentrated under reduced pressure togive 6.05 g of the title compound (95% purity, 66% yield).

LC-MS (method 2): R_(t)=1.15 min; MS (ESIpos): m/z=283 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.322 (0.70), 2.326 (0.98), 2.331(0.70), 2.518 (3.98), 2.522 (2.49), 2.617 (4.53), 2.636 (8.51), 2.654(5.01), 2.664 (0.95), 2.669 (1.08), 2.673 (0.79), 2.775 (4.04), 2.793(8.70), 2.810 (4.63), 3.283 (2.80), 3.290 (2.93), 3.301 (5.28), 3.308(5.17), 3.319 (2.83), 3.415 (2.93), 3.422 (3.21), 3.433 (5.10), 3.441(4.97), 3.451 (2.81), 3.459 (2.65), 3.565 (1.00), 7.306 (1.37), 7.310(1.59), 7.325 (3.65), 7.329 (3.63), 7.344 (4.38), 7.348 (4.20), 7.363(4.09), 7.366 (5.27), 7.369 (4.16), 7.382 (3.99), so 7.386 (6.05), 7.389(5.09), 7.397 (2.88), 7.401 (3.35), 7.403 (2.52), 7.408 (2.04), 7.416(3.57), 7.420 (3.98), 7.435 (1.75), 7.439 (1.57), 7.562 (4.89), 7.566(5.17), 7.582 (4.63), 7.587 (7.38), 7.590 (8.75), 7.594 (9.60), 7.610(7.00), 7.614 (7.87), 8.168 (2.75), 9.365 (2.45), 14.209 (5.81), 14.572(4.47), 16.420 (16.00), 16.440 (12.66).

Intermediate 5-40N-(3,5-difluoro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 5-32 and usingtert-butyl5-[(3,5-difluoro-2-methylphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate(intermediate 4-40, 5.15 g, 12.9 mmol) as the starting material, thetitle compound was prepared 3.93 g (95% purity, 97% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.224 (0.49), 2.028 (16.00), 2.297(1.29), 2.326 (0.54), 2.518 (2.09), 2.522 (1.34), 2.618 (1.01), 2.635(1.82), 2.652 (1.16), 2.664 (0.80), 2.669 (0.81), 2.673 (0.60), 2.771(1.01), 2.789 (1.71), 2.805 (1.01), 3.431 (1.58), 3.603 (0.45), 7.141(0.95), 7.162 (1.86), 7.181 (1.39), 7.211 (1.11), 7.230 (1.19), 7.235(1.14), 7.266 (0.46), 8.190 (0.92), 9.388 (0.92), 14.078 (1.39), 14.436(1.16), 16.343 (1.84), 16.357 (1.63).

LC-MS (method 2): R_(t)=0.52 min; MS (ESIpos): m/z=299 [M+H]⁺

Intermediate 5-41N-[3-fluoro-2-(trifluoromethyl)phenyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for intermediate 5-32 and usingtert-butyl5-{[3-fluoro-2-(trifluoromethyl)phenyl]carbamothioyl}-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate(intermediate 4-41, 1.96 g, 4.51 mmol) as the starting material, thetitle compound was prepared 770 mg (95% purity, 48% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.102 (0.57), 1.171 (0.45), 1.907(0.90), 1.986 (0.73), 2.322 (1.06), 2.326 (1.55), 2.332 (1.06), 2.518(6.80), 2.522 (4.48), 2.620 (4.40), 2.638 (8.47), 2.656 (4.89), 2.664(1.79), 2.668 (1.83), 2.673 (1.30), 2.786 (3.38), 2.803 (7.29), 2.821(3.95), 3.285 (2.36), 3.292 (3.09), 3.303 (4.97), 3.310 (5.13), 3.417(2.93), 3.424 (3.18), 3.435 (5.21), 3.442 (5.17), 3.454 (2.93), 3.461(2.61), 7.328 (4.60), 7.347 (5.13), 7.440 (1.79), 7.462 (2.52), 7.478(1.83), 7.489 (2.44), 7.499 (2.20), 7.527 (1.67), 7.725 (1.47), 7.746(2.73), 7.762 (3.38), 7.783 (2.97), 7.799 (2.12), 7.820 (0.90), 8.192(2.77), 9.421 (2.81), 14.230 (5.86), 14.690 (4.44), 16.227 (16.00),16.292 (11.85).

LC-MS (method 2): R, =0.53 min; MS (ESIpos): m/z=335 [M+H]⁺

Intermediate 5-424-hydroxy-2-oxo-N-[2-(trifluoromethyl)phenyl]-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for intermediate 5-32 and usingtert-butyl4-hydroxy-6-oxo-5-{[2-(trifluoromethyl)phenyl]carbamothioyl}-3,6-dihydropyridine-1(2H)-carboxylate(intermediate 4-42, 5.01 g, 76% purity, 9.14 mmol) as the startingmaterial, the title compound was prepared 3.92 g (71% purity, 96%yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.430 (11.28), 2.323 (0.79), 2.327(1.16), 2.331 (0.87), 2.518 (11.48), 2.523 (9.51), 2.623 (4.91), 2.641(8.53), 2.659 (5.55), 2.669 (1.87), 2.673 (1.39), 2.713 (0.46), 2.785(3.60), 2.803 (7.70), 2.821 (4.27), 3.288 (2.48), 3.295 (2.73), 3.306(4.91), 3.314 (5.14), 3.324 (3.74), 3.419 (3.08), 3.426 (3.33), 3.438(5.10), 3.445 (5.03), 3.455 (3.00), 3.463 (2.91), 7.469 (0.52), 7.488(1.06), 7.504 (2.06), 7.523 (3.39), 7.542 (3.43), 7.560 (3.75), 7.580(2.71), 7.592 (5.78), 7.611 (7.66), 7.641 (0.89), 7.660 (0.54), 7.674(0.75), 7.700 (2.75), 7.720 (3.68), 7.736 (3.75), 7.755 (3.50), 7.774(1.46), 7.790 (3.58), 7.808 (3.41), 7.823 (3.52), 7.841 (2.93), 8.176(2.50), 8.209 (0.56), 8.725 (0.44), 9.392 (2.45), 9.580 (0.71), 14.316(5.33), 14.768 (3.89), 16.371 (16.00), 16.414 (12.28).

LC-MS (method 2): R_(t)=0.48 min; MS (ESIpos): m/z=317 [M+H]⁺

Intermediate 5-43N-[3,5-difluoro-2-(difluoromethoxy)phenyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

To a solution of tert-butyl5-{[3,5-difluoro-2-(difluoromethoxy)phenyl]carbamothioyl}-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate(intermediate 4-43, 29.0 g, 64.4 mmol) in EtOAc (50 mL) was addedHCl/EtOAc (4 M, 200 mL, 12.4 eq). The mixture was stirred at 25° C. for20 min. The reaction mixture was concentrated under reduced pressure toremove solvent. The title compound was obtained as a yellow solid (22.36g, 63.1 mmol, 98.1% yield, 98.9% purity).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 14.88-14.41 (m, 1H), 9.48-8.22 (m,1H), 7.68-7.66 (m, 1H), 7.51-7.43 (m, 1H), 7.29-6.93 (m, 1H), 3.45-3.42(m, 1H), 3.41-3.34 (m, 1H), 2.81 (s, 1H), 2.66-2.62 (m, 1H)

Intermediate 5-44N-(3-chloro-4-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for intermediate 5-32 and usingtert-butyl5-[(3-chloro-4-fluoro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate(Intermediate 4-44, 5.96 g, 13.8 mmol) as the starting material, thetitle compound was prepared 2.59 g (95% purity, 54% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (1.05), 1.172 (2.14), 1.190(1.15), 1.987 (4.42), 2.322 (0.75), 2.327 (1.01), 2.331 (0.73), 2.518(4.34), 2.523 (2.70), 2.639 (1.37), 2.659 (1.11), 2.664 (1.27), 2.669(1.35), 2.673 (0.97), 2.790 (1.23), 3.302 (1.39), 3.429 (1.19), 3.778(16.00), 3.849 (0.59), 4.017 (0.91), 4.035 (0.91), 7.240 (0.50), 7.261(1.13), 7.285 (0.89), 7.699 (0.52), 7.738 (0.52), 7.754 (0.61), 8.187(0.65), 9.386 (0.56), 14.191 (1.01), 14.577 (1.07), 16.369 (2.04),16.389 (1.78).

LC-MS (method 2): R_(t)=1.22 min; MS (ESIpos): m/z=331 [M+H]⁺

Intermediate 5-45N-(5-fluoro-2-methylphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 5-32 and usingtert-butyl5-[(5-fluoro-2-methylphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate(intermediate 4-45, 2.00 g, 5.26 mmol) as the starting material, thetitle compound was prepared 1.03 g (75% purity, 52% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.574 (0.91), 1.600 (4.08), 1.611(4.36), 1.621 (4.40), 1.644 (3.70), 1.660 (3.04), 1.673 (2.64), 1.884(1.16), 1.898 (2.98), 1.913 (5.12), 1.927 (3.09), 1.942 (1.26), 2.138(16.00), 2.322 (0.51), 2.327 (0.75), 2.332 (0.55), 2.518 (3.14), 2.523(2.13), 2.625 (4.35), 2.635 (3.17), 2.651 (4.44), 2.665 (1.01), 2.669(1.16), 2.673 (0.89), 2.765 (0.50), 3.230 (1.99), 3.238 (2.74), 3.245(3.82), 3.250 (3.83), 3.256 (2.77), 3.265 (2.08), 3.308 (0.54), 3.416(0.48), 3.459 (3.64), 3.474 (6.28), 3.488 (3.47), 3.537 (4.28), 3.547(3.17), 3.561 (4.66), 7.090 (0.93), 7.255 (0.97), 7.278 (1.04), 7.328(0.86), 7.347 (1.23), 7.366 (0.82), 9.538 (1.45).

LC-MS (method 2): R_(t)=0.48 min; MS (ESIpos): m/z=281 [M+H]⁺

Intermediate 5-78N-(2-bromo-3-chlorophenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for intermediate 5-32 and usingtert-butyl5-[(2-bromo-3-chlorophenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate(Intermediate 4-78, 4.04 g, 99% purity, 8.66 mmol) as the startingmaterial, the title compound was prepared 3.27 g (97% purity, 99%yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.322 (1.82), 2.326 (2.41), 2.331(1.77), 2.336 (0.86), 2.518 (10.50), 2.522 (6.41), 2.621 (4.09), 2.639(7.77), 2.658 (4.82), 2.664 (2.59), 2.668 (2.73), 2.673 (1.95), 2.784(3.50), 2.802 (7.36), 2.820 (3.91), 3.287 (2.95), 3.295 (3.36), 3.306(6.00), 3.312 (6.95), 3.419 (2.73), 3.427 (3.05), 3.438 (4.86), 3.445(4.73), 3.456 (2.73), 3.463 (2.36), 5.758 (1.45), 7.422 (2.00), 7.441(5.86), 7.460 (7.45), 7.469 (15.68), 7.474 (7.59), 7.479 (8.23), 7.482(8.86), 7.489 (2.82), 7.493 (1.73), 7.502 (0.77), 7.569 (4.23), 7.574(3.95), 7.588 (3.27), 7.593 (3.23), 7.605 (3.55), 7.617 (3.59), 7.629(2.45), 7.638 (0.41), 8.189 (2.82), 9.409 (2.73), 14.230 (6.18), 14.630(5.05), 16.313 (16.00), 16.364 (11.64).

LC-MS (method 2): R, =0.51 min; MS (ESIneg): m/z=360 [M−H]⁻

Syntheses of Intermediate 6 Compounds Intermediate 6-14-({[3-(2-methoxyethoxy)pyridin-4-yl]methyl}amino)-2-oxo-N-phenyl-1,2,5,6-tetrahydropyridine-3-carbothioamide

A mixture of4-hydroxy-2-oxo-N-phenyl-1,2,5,6-tetrahydropyridine-3-carbothioamide(251 mg, 1.01 mmol—WO2016/120196) and1-[3-(2-methoxyethoxy)pyridin-4-yl]methanamine (184 mg, 1.01 mmol) inDMA (2 ml) was heated in a sealed vial at 120° C. for 90 mins using amicrowave. The reaction mixture was allowed to cool and purified bypreparative HPLC (basic method) to give the titled compound (108 mg, 28%yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.76 (s, 1H), 13.63-13.72 (m, 1H),8.39 (s, 1H), 8.24 (d, 1H), 7.68 (br s, 1H), 7.28-7.43 (m, 5H), 7.18 (t,1H), 4.65 (d, 2H), 4.19-4.32 (m, 2H), 3.68-3.73 (m, 2H), 3.32 (s, 3H),3.11-3.19 (m, 2H), 2.67-2.77 (m, 2H).

Intermediate 6-24-({[3-(3,3-dimethylbutoxy)pyridin-4-yl]methyl}amino)-N-(3-fluorophenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate6-1,4-hydroxy-2-oxo-N-phenyl-1,2,5,6-tetrahydropyridine-3-carbothioamide(271 mg, 1.02 mmol—WO2016/120196) and1-[3-(3,3-dimethylbutoxy)pyridin-4-yl]methanamine (293 mg, 1.41 mmol) asthe starting materials, the title compound was prepared 88.0 mg (18%yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.97 (s, 1H), 13.61 (br s, 1H), 8.42(s, 1H), 8.22 (d, 1H), 7.74 (br s, 1H), 7.55 (dt, 1H), 7.28-7.41 (m,2H), 7.15 (m, 1H), 7.01 (t, 1H), 4.63 (d, 2H), 4.14-4.24 (m, 2H),3.09-3.18 (m, 2H), 2.67-2.77 (m, 2H), 2.52-2.54 (m, 1H), 1.68-1.76 (m,2H), 0.89-0.99 (m, 9H).

Intermediate 6-34-({[3-(benzyloxy)pyridin-4-yl]methyl}amino)-N-(3-fluorophenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate6-1,4-hydroxy-2-oxo-N-phenyl-1,2,5,6-tetrahydropyridine-3-carbothioamide(250 mg, 939 μmol—WO2016/120196) and1-[3-(benzyloxy)pyridin-4-yl]methanamine (302 mg, 1.41 mmol) as thestarting materials, the title compound was prepared 86.0 mg (19% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.98 (s, 1H), 13.65 (br s, 1H), 8.44(s, 1H), 8.24 (d, 1H), 7.73 (br s, 1H), 7.48-7.56 (m, 3H), 7.30-7.43 (m,5H), 7.16 (m, 1H), 7.01 (m, 1H), 5.32 (s, 2H), 4.72 (d, 2H), 3.09 (m,2H), 2.67-2.74 (m, 2H).

Intermediate 6-4N-(3-fluorophenyl)-4-({[3-(2-hydroxy-2-methylpropoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,-hydroxy-2-oxo-N-phenyl-1,2,5,6-tetrahydropyridine-3-carbothioamide (250mg, 939 μmol—WO2016/120196) and1-{[4-(aminomethyl)pyridin-3-yl]oxy}-2-methylpropan-2-ol (276 mg, 1.41mmol—WO2016/120196) as the starting materials, the title compound wasprepared 158.0 mg (36% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.97 (s, 1H), 13.64 (br s, 1H), 8.35(s, 1H), 8.23 (d, 1H), 7.75 (br s, 1H), 7.54 (dt, 1H), 7.32-7.42 (m,1H), 7.27 (d, 1H), 7.16 (d, 1H), 7.02 (m, 1H), 4.67-4.79 (m, 3H), 3.91(s, 2H), 3.10-3.20 (m, 2H), 2.75 (t, 2H), 1.21-1.26 (m, 6H).

Intermediate 6-54-[({3-[2-(dimethylamino)ethoxy]pyridin-4-yl}methyl)amino]-N-(3-fluorophenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,-hydroxy-2-oxo-N-phenyl-1,2,5,6-tetrahydropyridine-3-carbothioamide (250mg, 939 μmol—WO2016/120196) and2-{[4-(aminomethyl)pyridin-3-yl]oxy}-N,N-dimethylethanamine (275 mg,1.41 mmol—WO2016/120196) as the starting materials, the title compoundwas prepared 175.0 mg (41% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.97 (s, 1H), 13.63 (br s, 1H), 8.41(s, 1H), 8.23 (d, 1H), 7.74 (br s, 1H), 7.54 (dt, 1H), 7.29-7.41 (m,2H), 7.16 (d, 1H), 7.02 (t, 1H), 4.65 (d, 2H), 4.17-4.26 (m, 2H),3.11-3.18 (m, 2H), 2.76 (t, 2H), 2.65-2.72 (m, 2H), 2.17-2.24 (m, 6H).

Intermediate 6-6N-(3-fluorophenyl)-4-({[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,-hydroxy-2-oxo-N-phenyl-1,2,5,6-tetrahydropyridine-3-carbothioamide (250mg, 939 μmol—WO2016/120196) and1-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methanamine (395 mg, 1.88)as the starting materials, the title compound was prepared 220 mg (51%yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.96 (s, 1H), 13.62 (br s, 1H),8.37-8.44 (m, 1H), 8.24 (d, 1H), 7.70-7.79 (m, 1H), 7.53 (dt, 1H), 7.39(m, 1H), 7.28 (d, 1H), 7.10-7.19 (m, 1H), 7.01 (t, 1H), 4.70 (d, 2H),4.00-4.06 (m, 2H), 3.11-3.21 (m, 5H), 2.74-2.78 (m, 2H), 1.24 (s, 6H).

Intermediate 6-7N-(3-fluorophenyl)-4-[({3-[2-methyl-2-(morpholin-4-yl)propoxy]pyridin-4-yl}methyl)amino]-2-oxo-1,2,5,6-tetrahydropyridin-carbothioamide

Using an analogous method as described for Intermediate 6-1,-hydroxy-2-oxo-N-phenyl-1,2,5,6-tetrahydropyridine-3-carbothioamide (250mg, 939 μmol—WO2016/120196) and1-{3-[2-methyl-2-(morpholin-4-yl)propoxy]pyridin-4-yl}methanamine (498mg, 1.88 mmol) as the starting materials, the title compound wasprepared 220 mg (46% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.96 (s, 1H), 13.60 (br s, 1H), 8.41(s, 1H), 8.23 (d, 1H), 7.75 (br s, 1H), 7.53 (dt, 1H), 7.38 (m, 1H),7.28 (d, 1H), 7.16 (m, 1H), 6.99-7.04 (m, 1H), 4.70 (d, 2H), 4.04 (s,2H), 3.48-3.57 (m, 4H), 3.15 (m, 2H), 2.72-2.79 (m, 2H), 2.56-2.63 (m,4H), 1.13 (s, 6H).

Intermediate 6-8N-(3-fluorophenyl)-4-{[(3-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,-hydroxy-2-oxo-N-phenyl-1,2,5,6-tetrahydropyridine-3-carbothioamide (250mg, 939 μmol—WO2016/120196) and1-(3-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}pyridin-4-yl)methanamine(416 mg, 1.88 mmol) as the starting materials, the title compound wasprepared 300 mg (58% yield).

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm]=14.88-15.08 (m, 1H), 13.43-13.80 (m,1H), 8.39 (s, 1H), 8.23 (d, 1H), 7.70-7.77 (m, 1H), 7.54 (br d, 1H),7.35-7.41 (m, 1H), 7.29 (d, 1H), 7.16 (d, 1H), 7.02 (d, 1H), 4.35 (t,1H), 4.17 (m, 1H), 3.97-4.03 (m, 1H), 3.11-3.17 (m, 2H), 2.89-3.00 (m,2H), 2.74 (t, 2H), 2.36 (s, 3H), 2.11-2.32 (m, 1H), 1.93-2.01 (m, 1H),1.59-1.74 (m, 4H).

Intermediate 6-9N-(3,5-difluorophenyl)-4-({[3-(2-methoxyethoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-1 ((1 g, 3.52 mmol) and1-[3-(2-methoxyethoxy)pyridin-4-yl]methanamine (961 mg, 5.28 mmol) asthe starting materials, the title compound was prepared 860 mg (55%yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=15.11 (s, 1H), 13.62 (t, 1H), 8.40(s, 1H), 8.24 (d, 1H), 7.80 (br s, 1H), 7.24-7.36 (m, 3H), 7.05 (tt,1H), 4.67 (d, 2H), 4.30 (m, 2H), 3.68-3.74 (m, 2H), 3.32 (s, 3H), 3.15(m, 2H), 2.74-2.81 (m, 2H).

Intermediate 6-10N-(3,5-difluorophenyl)-4-({[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-1 ((250 mg, 879 μmol) and1-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methanamine (370 mg, 1.76mmol) as the starting materials, the title compound was prepared 210 mg(43% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=15.11 (s, 1H), 13.60 (br s, 1H), 8.40(s, 1H), 8.24 (d, 1H), 7.80 (br s, 1H), 7.26-7.33 (m, 3H), 7.05 (tt,1H), 4.71 (d, 2H), 4.04 (s, 2H), 3.09-3.19 (m, 5H), 2.74-2.80 (m, 2H),1.17-1.26 (m, 7H).

Intermediate 6-11N-[2-(difluoromethoxy)phenyl]-4-({[3-(2-methoxyethoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-2 ((950 mg, 3.02 mmol) and1-[3-(2-methoxyethoxy)pyridin-4-yl]methanamine (826 mg, 4.53 mmol) asthe starting materials, the title compound was prepared 890 mg (47%yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.68 (s, 1H), 13.69 (brt, 1H), 8.40(s, 1H), 8.23 (d, 1H), 7.62-7.81 (m, 2H), 6.88-7.33 (m, 5H), 4.65 (d,2H), 4.26-4.31 (m, 2H), 3.67-3.74 (m, 3H), 3.31 (s, 3H), 3.15 (m, 2H),2.76 (t, 2H).

Intermediate 6-12N-(2-bromo-3-fluorophenyl)-4-({[3-(2-methoxyethoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-3 (250 mg, 724 μmol) and1-[3-(2-methoxyethoxy)pyridin-4-yl]methanamine (264 mg, 1.45 mmol) asthe starting materials, the title compound was prepared 58.8 mg (15%yield) after preparative HPLC purification (Instrument: WatersAutopurification system; Column: Waters XBridge C18 5μ 100×30 mm; EluentA: Water+0.1 Vol-% Formic acid (99%), Eluent B: Acetonitrile; Gradient:0.00-0.50 min 18% B (25 to 70 mL/min), 0.51-5.50 min 18-40% B (70mL/min), DAD scan: 210-400 nm).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.82 (s, 1H), 13.70 (brt, 1H), 8.40(s, 1H), 8.24 (d, 1H), 7.73 (br s, 1H), 7.21-7.43 (m, 4H), 4.66 (d, 2H),4.25-4.32 (m, 2H), 3.67-3.73 (m, 2H), 3.30-3.32 (m, 3H), 3.17 (br d,2H), 2.72-2.82 (m, 2H).

Intermediate 6-134-({[3-(2-methoxyethoxy)pyridin-4-yl]methyl}amino)-N-(2-methoxyphenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-4 (250 mg, 530 μmol) and1-[3-(2-methoxyethoxy)pyridin-4-yl]methanamine (262 mg, 1.44 mmol) asthe starting materials, the title compound was prepared 87 mg (26%yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.42 (s, 1H), 13.74 (brt, 1H), 8.39(s, 1H), 8.23 (d, 1H), 7.72 (m, 1H), 7.58 (br s, 1H), 7.30 (d, 1H), 7.17(t, 1H), 7.05 (m, 1H), 6.91 (m, 1H), 4.64 (d, 2H), 4.24-4.32 (m, 2H),3.67-3.78 (m, 5H), 3.32 (s, 3H), 3.14 (m, 2H), 2.69-2.78 (m, 2H).

Intermediate 6-144-({[3-(2-methoxyethoxy)pyridin-4-yl]methyl}amino)-2-oxo-N-[2-(trifluoromethoxy)phenyl]-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-5 (250 mg, 752 μmol) and1-[3-(2-methoxyethoxy)pyridin-4-yl]methanamine (274 mg, 1.50 mmol) asthe starting materials, the title compound was prepared 155 mg (39%yield).

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm]=14.94 (s, 1H), 13.70 (t, 1H), 8.40(s, 1H), 8.24 (d, 1H), 7.88 (m, 1H), 7.75 (br s, 1H), 7.30-7.43 (m, 4H),4.66 (d, 2H), 4.27-4.32 (m, 2H), 3.68-3.73 (m, 2H), 3.31 (s, 3H), 3.16(m, 2H), 2.78 (t, 2H).

Intermediate 6-15N-[2-(2,2-difluoroethyl)phenyl]-4-({[3-(2-methoxyethoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-6 (250 mg, 800 μmol) and1-[3-(2-methoxyethoxy)pyridin-4-yl]methanamine (292 mg, 1.60 mmol) asthe starting materials, the title compound was prepared 110 mg (27%yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.46 (s, 1H), 13.62 (brt, 1H), 8.39(s, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 8.23 (d, 1H), 7.67 (br s, 1H),7.20-7.39 (m, 5H), 6.17 (br d, 1H), 6.17 (t, 1H), 4.64 (d, 2H),4.26-4.31 (m, 2H), 3.67-3.73 (m, 2H), 3.31 (s, 2H), 3.17 (m, 2H),3.01-3.13 (m, 2H), 2.77 (t, 2H).

Intermediate 6-16N-(3-fluoro-2-methoxyphenyl)-4-({[3-(2-methoxyethoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-7 (250 mg, 844 μmol) and1-[3-(2-methoxyethoxy)pyridin-4-yl]methanamine (307 mg, 1.69 mmol) asthe starting materials, the title compound was prepared 130 mg (32%yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.74 (s, 1H), 13.71 (brt, 1H),8.36-8.44 (m, 1H), 8.24 (d, 1H), 7.64-7.74 (m, 2H), 7.31 (d, 1H),7.01-7.15 (m, 2H), 4.66 (br d, 2H), 4.24-4.35 (m, 2H), 3.67-3.84 (m,5H), 3.32 (s, 3H), 3.12-3.21 (m, 2H), 2.71-2.83 (m, 2H).

Intermediate 6-17N-(3-fluoro-2-methoxyphenyl)-4-({[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-7 (250 mg, 844 μmol) and1-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methanamine (355 mg, 1.69mmol) as the starting materials, the title compound was prepared 210 mg(51% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.74 (s, 1H), 13.69 (br t, 1H),8.34-8.41 (m, 1H), 8.24 (d, 1H), 7.64-7.73 (m, 2H), 7.29 (d, 1H),7.03-7.17 (m, 2H), 4.69 (d, 2H), 4.00-4.06 (m, 2H), 3.78 (d, 3H), 3.33(s, 4H), 3.12-3.21 (m, 5H), 2.73-2.78 (m, 2H), 2.52-2.53 (m, 1H),1.23-1.26 (m, 6H).

Intermediate 6-18N-[2-(difluoromethoxy)-3-fluorophenyl]-4-({[3-(2-methoxyethoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-8 (250 mg, 752 μmol) and1-[3-(2-methoxyethoxy)pyridin-4-yl]methanamine (274 mg, 1.50 mmol) asthe starting materials, the title compound was prepared 99 mg (25%yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.82 (s, 1H), 13.67 (brt, 1H), 8.40(s, 1H), 8.23 (d, 1H), 7.72 (br s, 1H), 7.56 (d, 1H), 7.22-7.34 (m, 3H),7.20 (s, 1H), 4.66 (d, 2H), 4.25-4.34 (m, 2H), 3.67-3.74 (m, 2H), 3.31(s, 3H), 3.15 (m, 2H), 2.78 (t, 2H).

Intermediate 6-19N-[2-(difluoromethoxy)-3-fluorophenyl]-4-({[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-8 (250 mg, 752 μmol) and1-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methanamine (316 mg, 1.50mmol) as the starting materials, the title compound was prepared 160 mg(41% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.81 (s, 1H), 13.56-13.75 (m, 1H),8.40 (s, 1H), 8.23 (d, 1H), 7.70-7.76 (m, 1H), 7.51-7.59 (m, 1H),7.25-7.32 (m, 3H), 7.01 (m, 1H), 4.67-4.74 (m, 2H), 3.96-4.11 (m, 2H),3.13-3.20 (m, 5H), 2.74-2.81 (m, 2H), 1.24 (s, 6H).

Intermediate 6-20N-(3-fluoro-2-methylphenyl)-4-({[3-(2-methoxyethoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-9 (250 mg, 892 μmol) and1-[3-(2-methoxyethoxy)pyridin-4-yl]methanamine (325 mg, 1.78 mmol) asthe starting materials, the title compound was prepared 140 mg (34%yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.52 (s, 1H), 13.68 (brt, 1H), 8.39(s, 1H), 8.23 (d, 1H), 7.68 (br s, 1H), 7.18-7.34 (m, 2H), 7.03-7.12 (m,2H), 4.64 (d, 2H), 4.26-4.32 (m, 2H), 3.68-3.74 (m, 2H), 3.31 (s, 3H),3.16 (m, 2H), 2.76 (t, 2H), 2.04 (d, 3H).

Intermediate 6-21N-(3-fluoro-2-methylphenyl)-4-({[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-9 (250 mg, 892 μmol) and1-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methanamine (375 mg, 1.78mmol) as the starting materials, the title compound was prepared 220 mg(52% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.51 (s, 1H), 13.65 (t, 1H), 8.39(s, 1H), 8.23 (d, 1H), 7.69 (br s, 1H), 7.28 (d, 1H), 7.18-7.26 (m, 1H),7.03-7.10 (m, 2H), 4.68 (d, 2H), 4.03 (s, 2H), 3.14-3.20 (m, 5H), 2.76(t, 2H), 2.04 (d, 3H), 1.22-1.26 (m, 6H).

Intermediate 6-22N-[2-(2,2-difluoroethyl)-3-fluorophenyl]-4-({[3-(2-methoxyethoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-10 (250 mg, 757 μmol) and1-[3-(2-methoxyethoxy)pyridin-4-yl]methanamine (276 mg, 1.51 mmol) asthe starting materials, the title compound was prepared 140 mg (36%yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.57 (s, 1H), 13.60 (brt, 1H), 8.39(s, 1H), 8.23 (d, 1H), 7.71 (brs, 1H), 7.29-7.40 (m, 2H), 7.10-7.19 (m,2H), 5.97-6.32 (m, 1H), 4.65 (d, 2H), 4.29 (m, 2H), 3.67-3.72 (m, 2H),3.31 (s, 3H), 3.04-3.20 (m, 4H), 2.74-2.81 (m, 2H).

Intermediate 6-23N-[2-(2,2-difluoroethyl)-3-fluorophenyl]-4-({[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-10 (250 mg, 757 μmol) and1-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methanamine (207 mg, 984μmol) as the starting materials, the title compound was prepared 190 mg(48% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.57 (s, 1H), 13.57 (br s, 1H), 8.40(s, 1H), 8.23 (d, 1H), 7.72 (br s, 1H), 7.32-7.43 (m, 1H), 7.28 (d, 1H),7.09-7.23 (m, 2H), 6.16 (br d, 1H), 5.98-6.32 (m, 1H), 4.64-4.74 (m,2H), 3.99-4.06 (m, 2H), 3.03-3.20 (m, 7H), 2.72-2.82 (m, 2H), 1.21-1.26(m, 6H).

Intermediate 6-24N-[3-fluoro-2-(prop-2-en-1-yloxy)phenyl]-4-({[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-11 (250 mg, 776 μmol) and1-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methanamine (212 mg, 1.01mmol) as the starting materials, the title compound was prepared 190 mg(48% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.70 (s, 1H), 13.69 (brt, 1H), 8.40(s, 1H), 8.24 (d, 1H), 7.73 (br s, 1H), 7.61 (m, 1H), 7.29 (d, 1H),7.02-7.12 (m, 2H), 5.97-6.07 (m, 1H), 5.30 (dq, 1H), 5.15-5.20 (m, 1H),4.69 (d, 2H), 4.48 (d, 2H), 3.99-4.05 (m, 2H), 3.12-3.21 (m, 5H), 2.76(t, 2H), 1.24 (s, 6H).

Intermediate 6-25N-(2-ethoxy-3-fluorophenyl)-4-({[3-(2-methoxyethoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-12 (250 mg, 806 μmol) and1-[3-(2-methoxyethoxy)pyridin-4-yl]methanamine (294 mg, 1.61 mmol) asthe starting materials, the title compound was prepared 134 mg (33%yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.73 (s, 1H), 13.72 (brt, 1H), 8.40(s, 1H), 8.24 (d, 1H), 7.68-7.75 (m, 2H), 7.31 (d, 1H), 7.01-7.11 (m,2H), 4.66 (d, 2H), 4.26-4.33 (m, 2H), 4.00 (q, 2H), 3.66-3.76 (m, 2H),3.32 (s, 3H), 3.09-3.21 (m, 2H), 2.72-2.81 (m, 2H), 1.26 (t, 3H).

Intermediate 6-26N-(2-ethoxy-3-fluorophenyl)-4-({[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-12 (250 mg, 806 μmol) and1-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methanamine (220 mg, 1.05mmol) as the starting materials, the title compound was prepared 200 mg(49% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.73 (s, 1H), 13.70 (br t, 1H),8.34-8.42 (m, 1H), 8.24 (d, 1H), 7.68-7.75 (m, 2H), 7.29 (d, 1H),7.01-7.11 (m, 2H), 4.69 (d, 2H), 3.92-4.08 (m, 4H), 3.04-3.19 (m, 5H),2.76 (t, 2H), 1.21-1.31 (m, 9H).

Intermediate 6-27N-[2-(2,2-difluoroethoxy)-3-fluorophenyl]-4-({[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-13 (250 mg, 722 μmol) and1-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methanamine (197 mg, 938μmol) as the starting materials, the title compound was prepared 220 mg(57% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.72 (s, 1H), 13.65 (br t, 1H),8.15-8.41 (m, 3H), 7.77 (br s, 1H), 7.58-7.65 (m, 1H), 7.28 (d, 1H),7.08-7.17 (m, 2H), 6.30 (tt, 1H), 4.70 (d, 2H), 4.17-4.29 (m, 2H), 4.04(s, 2H), 3.13-3.20 (m, 5H), 2.73-2.80 (m, 2H), 1.20-1.27 (m, 6H).

Intermediate 6-28N-(3,4-difluoro-2-methoxyphenyl)-4-({[3-(2-methoxyethoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-14 (250 mg, 795 μmol) and1-[3-(2-methoxyethoxy)pyridin-4-yl]methanamine (290 mg, 1.59 mmol) asthe starting materials, the title compound was prepared 115 mg (29%yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.64 (s, 1H), 13.67 (brt, 1H), 8.40(s, 1H), 8.23 (d, 1H), 7.71 (brs, 1H), 7.48-7.54 (m, 1H), 7.31 (d, 1H),7.10-7.19 (m, 1H), 4.65 (d, 2H), 4.25-4.33 (m, 2H), 3.84 (d, 3H),3.68-3.73 (m, 2H), 3.31 (s, 3H), 3.12-3.19 (m, 2H), 2.71-2.80 (m, 2H).

Intermediate 6-29N-(3,4-difluoro-2-methoxyphenyl)-4-({[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-14 (250 mg, 795 μmol) and1-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methanamine (335 mg, 1.59mmol) as the starting materials, the title compound was prepared 240 mg(60% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=14.64 (s, 1H), 13.65 (brt, 1H), 8.40(s, 1H), 8.24 (d, 1H), 7.72 (brs, 1H), 7.48-7.59 (m, 1H), 7.28 (d, 1H),7.10-7.19 (m, 1H), 4.69 (d, 2H), 4.03 (s, 2H), 3.84 (d, 3H), 3.09-3.20(m, 6H), 2.74-2.78 (m, 2H), 1.23-1.25 (m, 6H).

Intermediate 6-30N-(3,5-difluoro-2-methoxyphenyl)-4-({[3-(2-methoxyethoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-15 (250 mg, 795 μmol) and1-[3-(2-methoxyethoxy)pyridin-4-yl]methanamine (290 mg, 1.59 mmol) asthe starting materials, the title compound was prepared 160 mg (40%yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=15.06 (s, 1H), 13.67 (brt, 1H), 8.41(s, 1H), 8.24 (d, 1H), 7.91-7.97 (m, 1H), 7.78 (brs, 1H), 7.32 (d, 1H),7.14 (m, 1H), 4.67 (d, 2H), 4.27-4.33 (m, 2H), 3.70-3.77 (m, 5H), 3.32(s, 3H), 3.15 (m, 2H), 2.78 (t, 2H).

Intermediate 6-31N-(3,5-difluoro-2-methoxyphenyl)-4-({[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

Using an analogous method as described for Intermediate 6-1,intermediate 5-15 (250 mg, 795 μmol) and1-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methanamine (335 mg, 1.59mmol) as the starting materials, the title compound was prepared 250 mg(62% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=15.06 (s, 1H), 13.65 (t, 1H), 8.41(s, 1H), 8.24 (d, 1H), 7.93 (dt, 1H), 7.78 (br s, 1H), 7.29 (d, 1H),7.14 (m, 1H), 4.71 (d, 2H), 3.99-4.06 (m, 2H), 3.76 (d, 3H), 3.14-3.19(m, 5H), 2.78 (t, 2H), 1.24 (s, 6H).

Intermediate 6-32N-(3-chloro-2-methoxyphenyl)-4-({[3-(2-methoxyethoxy)pyridine-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

In a microwave tubeN-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide(intermediate 5-32, 200 mg, 96% purity, 614 μmol) and1-[3-(2-methoxyethoxy)pyridine-4-yl]methanamine (CAS: 1539076-88-4, 168mg, 921 μmol) were heated by microwave irradiation for 2 h at 120° C.The reaction mixture was diluted with 2 mL dimethyl sulfoxide, filteredand purified by preparative HPLC to give 119 mg of the title compound(99% purity, 40% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (0.67), 2.522 (0.42), 2.774(0.40), 3.315 (4.60), 3.331 (16.00), 3.695 (0.42), 3.718 (0.53), 4.285(0.42), 4.297 (0.44), 4.652 (0.47), 4.667 (0.46), 7.111 (0.56), 7.306(0.42), 7.310 (0.65), 8.233 (0.55), 8.244 (0.51), 8.400 (0.86), 14.789(0.48).

LC-MS (method 2): R_(t)=1.09 min; MS (ESIpos): m/z=477 [M+H]⁺

The examples in Table 2 were prepared analogous to the preparation ofintermediate 6-32.

TABLE 2 Inter- Structure mediate Name Analytical Data Starting materials6-33

¹H-NMR (400 MHz, DMSO-d6) δ (ppm]: 1.154 (0.97), 1.172 (2.04), 1.190 (104). 1.225 (2.64), 1.239 (16.00), 1.987 (3.28), 2.518 (1.65), 2.523(1.03), 2.756 (0.56), 2.774 (1.12), 2.790 (0.64), 3.141 (0.45), 3.149(0.54), 3.159 (0.92), 3.166 (3.09), 3.169 (13.83), 3.174 (1.38), 3.180(0.66), 3.188 (0.47), 3.711 (12.11), 3.965 (0.58), 4.017 (0.85), 4.035(4.63), 4.688 (1.29), 4.703 (1.29), 7.087 (0.77), 7.108 N-(3-chloro-2-methoxyphenyl)-4- hydroxy-2-oxo- 1,2,5,6- tetrahydropyridine-3carbothioamide (Intermediate 5-32, 306 mg, 978 μmol) 1-[3-(2-methoxy-2-methylpropoxy)pyridin- 4-yl]methanamine (intermediate 2-2, 329 mg, 1.57mmol) N-(3-chloro-2-methoxyphenyl)- (1.68), 7.128 (0.97),4-({[3-(2-methoxy-2- 7.284 (1.19), 7.288 methylpropoxy)pyridin-4-(2.04), 7.301 (1.21), yl]methyl}amino)-2-oxo-1,2,5,6- 7.304 (1.25),7.308 tetrahydropyridine-3- (0.93), 7.733 (0.75), carbothioamide 7.789(0.84), 7.793 (0.84), 7.809 (0.80), 7.813 (0.75), 8.234 (1.86), 8.246(1.58), 8.401 (2.57), 13.681 (0.52), 14.787 (1.29). LC-MS (method 1):R_(t) = 1.09 min; MS (ESIpos): m/z = 505 [M + H]⁺ 6-34

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (1.45), 1.172 (2.92), 1.190(1.40), 1.238 (16.00), 1.988 (5.19), 2.518 (0.95), 2.523 (0.62), 2.767(0.53), 2.784 (1.10), 2.801 (0.63), 3.150 (0.43), 3.167 (13.31), 4.017(1.22), 4.033 (4.42), 4.053 (0.41), 4.692 (1.27), 4.707 (1.26), 7.278(1.07), 7.290 (1.10), 7.330 (0.77), 7.350 (1.71), 7.370 (1.10), 7.497(0.86), 7.500 (1.19), 7.517 N-(2,3- dichlorophenyl)-4- hydroxy-2-oxo-1,2,5,6- tetrahydropyridine-3- carbothioamide (intermediate 5-34, 200mg, 631 μmol) 1-[3-(2-methoxy-2- methylpropoxy)pyridin- 4-yl]methanamine(intermediate 2-2, 146 mg, 694 μmol) N-(2,3-dichlorophenyl)-4-({[3-(0.80), 7.521 (0.89), (2-methoxy-2- 7.525 (1.00), 7.528methylpropoxy)pyridin-4- (0.78), 7.546 (0.79),yl]methyl}amino)-2-oxo-1,2,5,6- 7.549 (0.63), 7.749tetrahydropyridine-3- (0.74), 8.229 (1.72), carbothioamide 8.241 (1.70),8.398 (2.60), 13.655 (0.55), 14.890 (1.51). LC-MS (method 2): R_(t) =1.23 min; MS (ESIpos): m/z = 510 [M + H]⁺ 6-35

LC-MS (method 2): R_(t) = 1.19 min; MS (ESIpos): m/z = 487 [M + H]⁺N-(2-ethyl-3- fluorophenyl)-4- hydroxy-2-oxo- 1,2,5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-35, 200 mg, 679μmol) 1-[3-(2-methoxy-2- methylpropoxy)pyridi n-4-yl]methanamine(intermediate 2-2, 143 mg, 679 μmol) N-(2-ethyl-3-fluorophenyl) -4-({[3-(2-methoxy-2- methylpropoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6- tetrahydropyridine-3- carbothioamide6-36

LC-MS (method 2): R, = 1.22 min; MS (ESIpos): m/z = 490 [M + H]⁺N-(3-chloro-2- methylphenyl)-4- hydroxy-2-oxo- 1.2,5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-36. 389 mg. 1.31mmol) 1-[3-(2-methoxy-2- methylpropoxy)pyridin- 4-yl]methanamine(intermediate 2-2, 358 mg, 1.70 mmol) N-(3-chloro-2-methylphenyl)-4-({[3-(2-methoxy-2- methylpropoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6- tetrahydropyridine-3- carbothioamide6-37

N-(2-bromo-3-fluorophenyl)-4- ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.227(0.72), 1.239 (16.00), 2.518 (1.63), 2.523 (1.06), 2.768 (0.58), 2.784(1.19), 2.801 (0.69), 3.168 (13.69), 3.183 (0.50), 4.034 (4.29), 4.690(1.37), 4.705 (1.37), 7.234 (0.60), 7.238 (0.73), 7.255 (0.45), 7.259(0.46), 7.278 (1.10), 7.290 (1.13), 7.344 (0.41), 7.360 (1.13), 7.374(0.69), 7.389 (0.63), 7.394 (0.70), 7.409 (0.72), 7.739 (0.79), 8.230(1.63), N-(2-bromo-3- fluorophenyl)-4- hydroxy-2-oxo- 1.2.5.6-tetrahydropyridine-3- carbothioamide (intermediate 5-37, 217 mg. 96%purity, 603 μmol) 1-[3-(2-methoxy-2- methylpropoxy)pyridin-4-yl]methanamine (intermediate 2-2, 140 mg, 664 μmol) ({[3-(2-methoxy-2-8.242 (1.58), 8.398 methylpropoxy)pyridin-4- (2.58), 13.679yl]methyl}amino)-2-oxo-1,2,5,6- (0.60), 14.822 tetrahydropyridine-3-(1.55). carbothioamide LC-MS (method 2): R_(t) = 0.98 min; MS (ESIpos):m/z = 538 [M + H]⁺ 6-38

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.236 (16.00), 2.765 (0.55), 2.781(1.13), 2.798 (0.65), 3.141 (0.45), 3.151 (0.72), 3.166 (13.66), 4.033(4.35), 4.689 (1.31), 4.704 (1.30), 5.757 (0.89), 6.720 (0.71), 6.903(1.51), 7.085 (0.66), 7.276 (1.12), 7.289 (1.16), 7.294 (0.89), 7.314(1.77), 7.334 (1.09), 7.449 (0.94), 7.452 (1.05), 7.469 (0.77), 7.473(0.76), 7.581 (0.82), 7.585 (0.84), 7.601 N-[3-chloro-2-(difluoromethoxy)phe nyl]-4-hydroxy-2-oxo- 1,2,5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-38, 400 mg, 91%purity, 1.04 mmol) 1-[3-(2-methoxy-2- methylpropoxy)pyridin-4-yl]methanamine (intermediate 2-2, 395 mg, 1.88 mmol) N-[3-chloro-2-(0.74), 7.605 (0.69), (difluoromethoxy)phenyl]-4-({[3- 7.729 (0.75),8.229 (2-methoxy-2- (1.76), 8.240 (1.74), methylpropoxy)pyridin-4- 8.399(2.69), yl]methyl}amino)-2-oxo-1,2,5,6- 13.614 (0.44),tetrahydropyridine-3- 14.784 (1.03). carbothioamide LC-MS (method 2):R_(t) = 1.20 min; MS (ESIpos): m/z = 542 [M + H]⁺ 6-39

¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.036 (0.90), 1.053 (2.03), 1.071(1.03), 1.240 (16.00), 2.518 (0.53), 2.755 (0.52), 2.772 (1.05), 2.788(0.60), 3.152 (0.45), 3.169 (13.97), 3.423 (0.46), 3.436 (0.48), 3.440(0.45), 3.452 (0.45), 4.034 (4.08), 4.356 (0.61), 4.685 (1.23), 4.700(1.22), 7.239 (0.68), 7.243 (0.68), 7.258 (0.59), 7.263 (0.58), 7.282(1.03), 7.294 (1.07), 7.304 (0.52), 7.308 (0.56), 7.323 (0.70), 7.327(0.76), 7.342 (0.41), 7.499 (0.96), N-(2-chlorophenyl)- 4-hydroxy-2-oxo-1.2,5,6- tetrahydropyridine-3- carbothioamide (intermediate 5-39, 600mg, 2.12 mmol) 1-[3-(2-methoxy-2- methylpropoxy)pyridin-4-yl]methanamine (intermediate 2-2, 535 mg, 2.55 mmol)N-(2-chlorophenyl)-4-({[3-(2- 7.502 (1.01), 7.519 methoxy-2- (0.87),7.523 (0.83), methylpropoxy)pyridin-4- 7.567 (0.77), 7.572yl]methyl}amino)-2-oxo-1,2,5,6- (0.78), 7.587 (0.68),tetrahydropyridine-3- 7.591 (0.65), 7.703 carbothioamide (0.70), 8.230(1.77), 8.242 (1.66), 8.397 (2.53), 13.694 (0.51), 14.747 (1.35). LC-MS(method 1): R_(t) = 1.02 min; MS (ESIpos): m/z = 475 [M + H]⁺ 6-40

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.237 (16.00), 2.011 (3.18), 2.518(0.50), 2.756 (0.59), 2.774 (1.20), 2.790 (0.68), 3.145 (0.48), 3.153(0.59), 3.167 (13.73), 3.178 (0.63), 3.183 (0.50), 4.034 (4.29), 4.684(1.36), 4.698 (1.35), 7.095 (0.40), 7.102 (0.68), 7.113 (0.57), 7.125(0.50), 7.138 (0.52), 7.277 (1.10), 7.289 (1.12), 7.745 (0.79), 8.230(1.64), 8.242 (1.56), 8.398 (2.59), 13.626 (0.49), 14.680 (1.24).N-(3,5-difluoro-2- methylphenyl)-4- hydroxy-2-oxo- 1,2.5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-40, 243 mg. 814μmol) 1-[3-(2-methoxy-2- methylpropoxy)pyridin- 4-yl]methanamine(intermediate 2-2, 222 mg, 1.06 mmol) N-(3,5-difluoro-2- LC-MS (method2): methylphenyl)-4-({[3-(2- R_(t) = 1.05 min; MS methoxy-2- (ESIpos):m/z = 491 methylpropoxy)pyridin-4- [M + H]⁺yl]methyl}amino)-2-oxo-1,2,5,6- tetrahydropyridine-3- carbothioamide6-41

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.232 (16.00), 2.518 (0.78), 2.523(0.56), 2.773 (0.54), 2.790 (1.12), 2.807 (0.64), 3.151 (0.45), 3.163(15.20), 3.174 (0.81), 3.183 (0.44), 4.028 (4.27), 4.682 (1.26), 4 696(1.25), 7.257 (0.66), 7.275 (1.58), 7.287 (1.07), 7.357 (0.41), 7.677(0.47), 7.692 (0.47), 7.739 (0.74), 8.228 (1.38), 8.240 (1.34), 8.397(2.17), 13.611 (0.56), 14.915 (1.21). N-[3-fluoro-2-(trifluoromethyl)phen yl]-4-hydroxy-2-oxo- 1.2,5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-41, 200 mg, 598μmol) 1-[3-(2-methoxy-2- methylpropoxy)pyridin- 4-yl]methanamine(intermediate 2-2, 126 mg, 598 μmol) N-[3-fluoro-2- LC-MS (method 2):(trifluoromethyl)phenyl]-4-({[3- R_(t) = 1.17 min; MS (2-methoxy-2-(ESIpos): m/z = 527 methylpropoxy)pyridin-4- [M + H]⁺yl]methyl}amino)-2-oxo-1,2,5,6- tetrahydropyridine-3- carbothioamide6-42

¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.234 (16.00), 2.618 (1.32), 2.523(0.85), 2.768 (0.56), 2.784 (1.14), 2.801 (0.64), 3.165 (14.78), 3.183(0.45), 3.190 (0.44). 4.030 (4.19), 4.681 (1.30), 4.695 (1.28), 7.282(1.07), 7.294 (1.09), 7.426 (0.67), 7.445 (0.41), 7.540 (0.59), 7.560(0.87), 7.628 (0.47), 7.646 (0.64), 7.704 (0.77), 7.721 (0.79), 7.740(0.66), 8.230 (1.70), 4-hydroxy-2-oxo-N- [2-(trifluoromethyl)phenyl]-1,2,5.6- tetrahydropyridine-3- carbothioamide (intermediate 5-42,200 mg, 71% purity, 449 μmol) 1-[3-(2-methoxy-2- methylpropoxy)pyridin-4-yl]methanamine (intermediate 2-2, 104 mg, 494 μmol)4-({[3-(2-methoxy-2- 8.242 (1.59), 8.397 methylpropoxy)pyridin-4-(2.51), 13.693 yl]methyl}amino)-2-oxo-N-[2- (0.58), 14.908(trifluoromethyl)phenyl]-1,2,5,6- (1.34). tetrahydropyridine-3- LC-MS(method 2): carbothioamide R_(t) = 1.16 min; MS (ESIpos): m/z = 509 [M +H]⁺ 6-43

¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.238 (16.00), 2.518 (0.86), 2.523(0.55), 2.774 (0.47), 2.791 (0.97), 2.807 (0.57), 3.144 (0.44), 3.154(0.74), 3.166 (14.85), 3.178 (0.45), 4.038 (4.00), 4.706 (1.14), 4.720(1.14), 6.838 (0.47), 7.019 (0.92), 7.201 (0.43), 7.280 (0.97), 7.292(1.00), 7.329 (0.41), 7.799 (0.65), 8.233 (1.54), 8.245 (1.53), 8.406(2.34), 13.627 (0.47), 15.118 (1.13). N-[2- (difluoromethoxy)-3.5-difluorophenyl]-4- hydroxy-2-oxo- 1.2,5,6- tetrahydropyridine-3-carbothioamide (intermediate 5-43, 200 mg. 571 μmol) 1-[3-(2-methoxy-2-methylpropoxy)pyridin- 4-yl]methanamine (intermediate 2-2, 216 mg, 1.03mmol) N-[2-(difluoromethoxy)-3,5- LC-MS (method 2):difluorophenyl]-4-({[3-(2- R_(t) = 1.21 min; MS methoxy-2- (ESIpos): m/z= 543 methylpropoxy)pyridin-4- [M + H]⁺ yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3- carbothioamide 6-44

¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.165 (1.13), 1.206 (0.57), 1.225(5.98), 1.236 (16.00), 2.518 (1.43), 2.523 (0.90), 2.759 (0.56), 2.776(1.12), 2.793 (0.63), 3.104 (0.44), 3.136 (0.75), 3.144 (0.55), 3.150(0.99), 3.167 (15.10), 3.176 (1.31), 3.183 (0.65), 3.722 (0.93), 3.749(11.02), 3.967 (1.29), 4.034 (4.12), 4.687 (1.26), N-(3-chloro-4-fluoro-2-methoxyphenyl)-4- hydroxy-2-oxo- 1.2,5,6- tetrahydropyridine-3-carbothioamide (intermediate 5-44, 150 mg, 453 μmol) 1-[3-(2-methoxy-2-methylpropoxy)pyridin- 4-yl]methanamine (intermediate 2-2, 153 mg, 726μmol) N-(3-chloro-4-fluoro-2- 4.702 (intermediate 2-2, (1.25), 5.758(0.51), methoxyphenyl)-4-({[3-(2- 7.174 (0.85), 7.196 methoxy-2- (1.48),7.219 (0.91), methylpropoxy)pyridin-4- 7.282 (1.05), 7.294yl]methyl}amino)-2-oxo-1,2,5,6- (1.07), 7.672 (0.73),tetrahydropyridine-3- 7.688 (0.77), 7.695 carbothioamide (0.74), 7.710(0.70), 7.739 (0.75), 8.162 (0.44), 8.174 (0.40), 8.231 (1.70), 8.243(2.00), 8.399 (2.49), 13.640 (0.49), 14.707 (1.05). LC-MS (method 2):R_(t) = 1.12 min; MS (ESIneg): m/z = 521 [M-H]- 6-45

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.198 (0.64), 1.215 (0.73), 1.239(16.00), 2.118 (4.83), 2.518 (2.13), 2.522 (1.28), 2.744 (0.55), 2.761(1.11), 2.777 (0.64), 3.139 (0.44), 3.146 (0.53), 3.156 (0.86), 3.169(12.65), 3.178 (0.62), 3.504 (0.44), 4.034 (4.10), 4.676 (1.26), 4.690(1.25), 6.979 (0.60), 6.985 N-(5-fluoro-2- methylphenyl)-4-hydroxy-2-oxo- 1.2.5,6- tetrahydropyridine-3- carbothioamide(intermediate 5-45, 200 mg. 91% purity, 649 μmol) 1-[3-(2-methoxy-2-methylpropoxy)pyridi n-4-yl]methanamine (intermediate 2-2, 246 mg, 1.17mmol) N-(5-fluoro-2-methylphenyl)-4- (0.66), 7.236 (0.59),({[3-(2-methoxy-2- 7.242 (0.60), 7.255 methylpropoxy)pyridin-4- (0.55),7.262 (0.67), yl]methyl}amino)-2-oxo-1,2,5,6- 7.269 (0.91), 7.282tetrahydropyridine-3- (1.00), 7.294 (1.23), carbothioamide 7.495 (0.50),7.697 (0.72), 7.934 (0.44), 8.232 (1.16), 8.244 (1.11), 8.398 (1.87),13.655 (0.43), 14.595 (1.05), LC-MS (method 2): R_(t) = 1.16 min; MS(ESIpos): m/z = 473 [M + H]⁺ 6-46

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (0.45). 2.786 (0.74), 2.803(0.43), 3.164 (0.50), 3.171 (0.47), 3.312 (9.65), 3.330 (16.00), 3.690(0.77). 3.698 (0.65), 3.701 (0.84), 3.705 (0.65), 3.713 (0.84), 4.281(0.80), 4.289 (0.61), 4.292 (0.84), 4.296 (0.63), 4.304 (0.75), 4.654(0.85), 4.669 (0.86), 7.302 (0.69), 7.314 (0.70), 7.331 (0.52), 7.352(1.17), 7.372 (0.74), 7.497 (0.58), 7.501 (0.79), 7.518 N-(2,3-dichlorophenyl)-4- hydroxy-2-oxo- 1,2,5,6- tetrahydropyridine-3-carbothioamide (intermediate 5-34, 200 mg, 631 μmol) 1-[3-(2-methoxyethoxy)pyridine- 4-yl]methanamine (CAS:1539076-88-4, 126 mg, 694μmol) N-(2,3-dichlorophenyl)-4-({[3- (0.53), 7.521 (0.57),(2-methoxyethoxy)pyridin-4- 7.530 (0.64), 7.533yl]methyl}amino)-2-oxo-1,2,5,6- (0.52), 7.549 (0.51),tetrahydropyridine-3- 7.553 (0.42), 7.743 carbothioamide (0.48), 8.228(1.03), 8.240 (0.96), 8.397 (1.58), 14.892 (0.96). LC-MS (method 2):R_(t) = 1.13 min; MS (ESIpos): m/z = 482 [M + H]⁺ 6-47

¹H-NMR (400 MHz, ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.518 (1.57), 2.523(1.01), 2.768 (0.60), 2.785 (1.19), 2.801 (0.69), 3.145 (0.45), 3.153(0.51), 3.162 (0.81), 3.169 (0.77), 3.179 (0.44), 3.308 (16.00), 3.685(1.24), 3.693 (1.06), 3.697 (1.38), 3.700 (1.06), 3.708 (1.34), 4.277(1.31), 4.285 (1.01), 4.289 (1.37), 4.293 (1.02), 4.300 (1.21), 4.645(1.41), 4.659 (1.41), 7.303 (1.14), 7.315 (1.16), 4-hydroxy-2-oxo-N-[2-(trifluoromethyl)phen yl]-1.2.5.6- tetrahydropyridine-3-carbothioamide (intermediate 5-42, 200 mg, 71% purity, 449 μmol)methoxyethoxy)pyridine- 4-yl]methanamine (CAS:1539076-88-4, 90.0 mg, 494μmol) 4-({[3-(2- 7.427 (0.70), 7.447 methoxyethoxy)pyridin-4- (0.43),7.549 (0.60), yl]methyl}amino)-2-oxo-N-[2- 7.568 (0.91), 7.630(trifluoromethyl)phenyl]-1,2,5,6- (0.49), 7.649 (0.66),tetrahydropyridine-3- 7.699 (0.78), 7.722 carbothioamide (0.78), 7.742(0.69), 8.229 (1.85), 8.241 (1.78), 8.396 (2.79), 13.712 (0.59), 14.911(1.39). LC-MS (method 2): R_(t) = 1.07 min; MS (ESIpos): m/z = 481 [M +H]⁺ 6-48

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.657 (1.46), 1.667 (1.66), 1.678(1.69). 1.688 (1.46), 1.701 (0.93), 1.708 (0.74), 1.965 (0.64), 2.181(1.06), 2.190 (0.72), 2.202 (0.94), 2.276 (1.15), 2.326 (0.67), 2.357(12.78), 2.362 (6.68), 2.369 (3.35), 2.375 (0.68), 2.518 (2.02), 2.522(1.40), 2.746 (0.67), 2.762 (1.33), 2.779 (0.84), 2.946 (0.74),N-(3-chloro-2- methoxyphenyl)-4- hydroxy-2-oxo- 1,2,5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-32, 200 mg, 639μmol) 1-(3-{[(2S)-1- methylpyrrolidin-2- yl]methoxy}pyridin-4-yl)methanamine (intermediate 2-4, 226 mg, 1.02 mmol)N-(3-chloro-2-methoxyphenyl)- 2.951 (0.84), 2.9604-{[(3-{[(2S)-1-methylpyrrolidin- (0.74), 3.050 (0.80),2-yl]methoxy}pyridin-4- 3.144 (0.65), 3.153yl)methyl]amino}-2-oxo-1,2,5,6- (1.06), 3.160 (1.03),tetrahydropyridine-3- 3.423 (1.86), 3.711 carbothioamide (16.00), 3.974(1.12), 3.989 (0.94), 3.998 (1.15), 4.012 (0.88), 4.146 (0.90), 4.159(0.93), 4.170 (0.71), 4.183 (0.68), 4.646 (1.69), 4.661 (1.70), 7.088(1.29), 7.109 (2.50), 7.129 (1.44), 7.284 (1.58), 7.288 (1.66), 7.295(1.59), 7.304 (1.87), 7.308 (2.56), 7.725 (1.02), 7.794 (1.18), 7.797(1.20), 7.814 (1.13), 7.818 (1.06), 8.172 (0.68), 8.224 (2.43), 8.236(2.27), 8.240 (0.84), 8.266 (0.85), 8.286 (0.88), 8.393 (3.52), 13.672(0.70), 14.785 (1.64). LC-MS (method 1): R_(t) = 0.82 min; MS (ESIneg):m/z = 514 [M − H]⁻ 6-49

LC-MS (method 2): R_(t) = 1.13 min; MS (ESIpos): m/z = 484 [M + H]⁺N-(3-fluoro-2- methylphenyl)-4- hydroxy-2-oxo- 1,2,5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-9, 250 mg. 892μmol) yl]methoxy}pyridin-4- yl)methanamine (intermediate 2-4, 197 mg,892 μmol) N-(3-fluoro-2-methylphenyl)-4-{[(3-{[(2S)-1-methylpyrrolidin-2- yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6- tetrahydropyridine-3- carbothioamide6-50

¹H-NMR (400 MHz, ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.636 (0.49), 1.654(1.34), 1.670 (1.64), 1.679 (1.46), 1.688 (1.08), 1.701 (0.83), 1.709(0.53), 1.952 (0.50), 1.961 (0.52), 1.973 (0.62), 1.984 (0.42), 1.992(0.41), 2.160 (0.48), 2.182 (1.23), 2.203 (1.04), 2.355 (16.00), 2.518(2.48), 2.522 (1.55), 2.605 (0.55), 2.619 (0.61), 2.625 (0.74), 2.639(0.62), 2.751 (0.97), 2.768 (1.95), 2.785 (1.18), 2.929 (0.47), 2.936N-[3-chloro-2- (difluoromethoxy)phe nyl]-4-hydroxy-2-oxo- 1.2,5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-38. 150 mg, 430μmol) 1-(3-{[(2S)-1- methylpyrrolidin-2- yl]methoxy}pyridin-4-yl)methanamine (intermediate 2-4, 95.2 mg, 430 μmol) N-[3-chloro-2-(0.48), 2.945 (0.60), (difluoromethoxy)phenyl]-4-{[(3- 2.951 (0.79),2.960 {[(2S)-1-methylpyrrolidin-2- (0.55), 2.967 (0.56),yl]methoxy}pyridin-4- 3.142 (0.94), 3.151yl)methyl]amino}-2-oxo-1,2,5,6- (1.51), 3.158 (1.47),tetrahydropyridine-3- 3.971 (0.93), 3.985 carbothioamide (0.95), 3.994(1.18), 4.009 (1.10), 4.141 (1.17), 4.154 (1.21), 4.165 (0.97), 4.178(0.91), 4.646 (2.35), 4.660 (2.34), 6.721 (1.40), 6.903 (3.00), 7.086(1.33), 7.282 (2.03), 7.294 (3.12), 7.315 (3.04), 7.336 (1.88), 7.451(1.80), 7.455 (1.97), 7.471 (1.45), 7.475 (1.40), 7.583 (1.58), 7.587(1.54), 7.603 (1.39), 7.607 (1.26), 7.721 (1.44), 8.219 (3.12), 8.230(2.82), 8.391 (4.66), 13.605 (0.88), 14.779 (2.00). LC-MS (method 2):R_(t) = 1.18 min; MS (ESIpos): m/z = 553 [M + H]⁺ 6-51

¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.639 (0.46), 1.655 (1.32), 1.669(1.53), 1.673 (1.53), 1.679 (1.43), 1.689 (1.12), 1.702 (0.80), 1.710(0.52), 1.954 (0.51), 1.963 (0.51), 1.974 (0.62), 1.986 (0.47), 1.995(0.52), 2.010 (5.78), 2.013 (5.80), 2.160 (0.47), 2.183 (1.13), 2.203(1.00), 2.356 (16.00), 2.518 (1.01), 2.523 (0.66), 2.608 (0.49), 2.615(0.48), 2.622 (0.56), 2.629 (0.70), 2.644 (0.58), 2.746 (0.89), 2.762(1.78), 2.779 (1.13), 2.931 (0.44), 2.938 (0.47), N-(3,5-difluoro-2-methylphenyl)-4- hydroxy-2-oxo- 1.2,5,6- tetrahydropyridine-3-carbothioamide (intermediate 5-40, 235 mg, 787 μmol) 1-(3-{[(2S)-1 -methylpyrrolidin-2- yl]methoxy}pyridin-4- yl)methanamine (intermediate2-4, 226 mg, 1.02 mmol) N-(3,5-difluoro-2- 2.947 (0.59), 2.953methylphenyl)-4-{[(3-{[(2S)-1- (0.76), 2.964 (0.52), methylpyrrolidin-2-2.969 (0.53), 3.141 yl]methoxy}pyridin-4- (0.80), 3.148 (0.91),yl)methyl]amino}-2-oxo-1,2,5,6- 3.157 (1.49), 3.164tetrahydropyridine-3- (1.46), 3.174 (0.80), carbothioamide 3.181 (0.68),3.969 (0.91), 3.983 (0.95), 3.993 (1.16), 4.008 (1.11), 4.144 (1.18),4.156 (1.20), 4.167 (0.97), 4.181 (0.93), 4.641 (2.34), 4.656 (2.36),7.072 (0.46), 7.079 (0.64), 7.096 (0.75), 7.103 (1.16), 7.119 (1.23),7.126 (1.28), 7.142 (0.89), 7.286 (2.03), 7.298 (2.05), 7.738 (1.42),8.221 (3.12), 8.232 (2.86), 8.390 (4.67), 13.604 (0.48), 13.618 (0.89),13.631 (0.45), 14.679 (2.23). LC-MS (method 1): R_(t) = 0.72 min; MS(ESIpos): m/z = 502 [M + H]⁺ 6-52

LC-MS (method 2): R_(t) = 1.13 min; MS (ESIpos): m/z = 475 [M + H]⁺N-(3-chloro-2- methylphenyl)-4- hydroxy-2-oxo- 1,2,5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-36, 379 mg, 1.28mmol) 2-{(4-(aminomethyl) pyridin-3-yl]oxy}-N,N- dimethylethan-1- amine(CAS 1513085-25-0), 324 mg, 1.66 mmol) N-(3-chloro-2-methylphenyl)-4-[({3-[2- (dimethylamino)ethoxy]pyridin- 4-yl}methyhamino]-2-oxo-1,2,5,6-tetrahydropyridine-3- carbothioamide 6-53

LC-MS (method 2): R_(t) = 1.03 min; MS (ESIpos): m/z = 474 [M + H]⁺N-(3-fluoro-2- methoxyphenyl)-4- hydroxy-2-oxo- 1.2.5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-7, 200 mg, 675μmol) 2-{[4- (aminomethyl)pyridin- 3-yl]oxy}-N,N- dimethylethan-1- amine(CAS 1513085-25-0), 198 mg, 1.01 mmol) 4-[({3-[2-(dimethylamino)ethoxy]pyridin- 4-yl}methyl)amino]-N-(3-fluoro-2-methoxyphenyl)-2-oxo- 1,2,5,6-tetrahydropyridine-3- carbothioamide6-54

¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.215 (16.00), 2.518 (1.03), 2.523(0.67), 2.659 (0.92), 2.674 (1.98), 2.689 (0.86), 2.758 (0.46), 2.774(0.92), 2.791 (0.53), 3.143 (0.40), 3.153 (0.63), 3.159 (0.60), 3.710(9.07), 4.222 (0.86), 4.237 (1.76), 4.251 (0.81), 4.643 (1.07), 4.658(1.05), 7.089 (0.60), 7.109 (1.28), 7.129 (0.74), 7.284 (0.86), 7.288(0.90), 7.304 (1.44), 7.308 (0.82), 7.315 (0.91), 7.725 (0.61), 7.795(0.66), 7.798 (0.67), 7.815 N-(3-chloro-2- methoxyphenyl)-4-hydroxy-2-oxo- 1.2,5,6- tetrahydropyridine-3- carbothioamide(intermediate 5-32. 200 mg. 96% purity. 614μmol)2-{[4-(aminomethyl)pyridin 3-yl]oxy}-N,N- dimethylethan-1- amine(CAS 1513085-25-0), 180 mg, 921 μmol) N-(3-chloro-2-methoxyphenyl)-(0.64), 7.818 (0.60), 4-[({3-[2-(dimethylamino) 8.224 (1.32), 8.236ethoxy]pyridin-4-yl}methyhamino]-2- (1.27), 8.405 (2.03),oxo-1,2,5,6-tetrahydropyridine-3- 13.687 (0.43), carbothioamide 14.787(1.12), LC-MS (method 2): R_(t) = 1.09 min; MS (ESIpos): m/z = 491 [M +H]⁺ 6-55

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.012 (2.58), 2.214 (16.00), 2.518(0.38), 2.523 (0.24), 2.658 (0.85), 2.672 (1.89), 2.687 (0.86), 2.758(0.47), 2.775 (0.96), 2.791 (0.55), 3.140 (0.36), 3.148 (0.41), 3.157(0.65), 3.164 (0.63), 3.174 (0.36), 3.181 (0.31), 4.219 (0.88), 4.234(1.80), 4.248 (0.85), 4.638 (1.11), 4.653 (1.10), 7.071 (0.20), 7.077(0.28), 7.094 (0.34), 7.101 (0.50), 7.120 (0.54), 7.125 (0.64), 7.145(0.38), 7.294 (0.88), 7.306 N-(3,5-difluoro-2- methylphenyl)-4-hydroxy-2-oxo- 1.2,5,6- tetrahydropyridine-3- carbothioamide(intermediate 5-40. 219 mg, 733 μmol) 2-{(4- (aminomethyl)pyridin-3-yl]oxy}-N,N- dimethylethan-1- amine (CAS 1513085-25-0), 186 mg, 953μmol) N-(3,5-difluoro-2- (0.90), 7.736 (0.63), methylphenyl)-4-[({3-[2-8.221 (1.25), 8.232 (dimethylamino)ethoxy]pyridin- (1.16), 8.403 (1.96),4-yl}methyhamino]-2-oxo- 13.619 (0.21), 1,2,5,6-tetrahydropyridine-3-13.634 (0.39), carbothioamide 13.648 (0.20), 14.683 (1.00). LC-MS(method 1): R_(t) = 0.68 min; MS (ESIpos): m/z = 476 [M + H]⁺ 6-56

LC-MS (method 2): R_(t) = 1.05 min; MS (ESIpos): m/z = 458 [M + H]⁺N-(3-fluoro-2- methylphenyl)-4- hydroxy-2-oxo- 1.2,5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-9, 200 mg, 713μmol) 2-{[4-(aminomethyl) pyridin-3-yl]oxy}-N,N- dimethylethan-1- amine(CAS 1513085-25-0), 139 mg, 713 μmol) 4-[({3-[2-(dimethylamino)ethoxy]pyridin- 4-yl}methyl)amino]-N-(3-fluoro-2-methylphenyl)-2-oxo-1,2,5,6- tetrahydropyridine-3- carbothioamide 6-57

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.035 (8.82), 1.053 (16.00), 1.070(9.01), 1.073 (2.17), 1.100 (0.68), 1.170 (15.23), 1.178 (5.66), 1.189(0.55), 1.952 (0.63), 1.969 (1.09), 1.987 (1.91), 2.005 (0.84), 2.427(0.49), 2.518 (0.83), 2.522 (0.54), 2.735 (0.53), 2.751 (1.07), 2.768(0.72), 3.055 (1.11), 3.083 (0.55), 3.107 (12.25), 3.116 (4.09), 3.131(0.43), 3.138 (0.47), 3.147 (0.71), 3.154 (0.67), 3.405 (1.40),N-(3-fluoro-2- methoxyphenyl)-4- hydroxy-2-oxo- 1.2.5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-7, 200 mg, 675μmol) 1-[3-(3-methoxy-3- methylbutoxy)pyridin- 4-yl]methanamine(intermediate 2-57, 151 mg, 675 μmol) N-(3-fluoro-2-methoxyphenyl)-3.418 (1.58), 3.422 4-({[3-(3-methoxy-3- (4.15), 3.435 (4.25),methylbutoxy)pyridin-4- 3.440 (4.04), 3.452yl]methyl}amino)-2-oxo-1,2,5,6- (4.12), 3.457 (1.28),tetrahydropyridine-3- 3.469 (1.19), 3.713 carbothioamide (1.75), 3.715(1.84), 3.780 (5.82), 3.783 (5.94), 3.799 (1.04), 3.829 (3.65), 3.833(3.58), 3.858 (1.75), 3.860 (1.69), 4.168 (0.63), 4.188 (0.97), 4.206(1.70), 4.224 (1.08), 4.241 (0.41), 4.343 (2.69), 4.355 (5.17), 4.368(2.46), 4.629 (1.18), 4.643 (1.16), 7.047 (0.57), 7.062 (0.69), 7.066(0.88), 7.073 (0.74), 7.082 (0.63), 7.095 (0.67), 7.100 (0.75), 7.116(0.51), 7.120 (0.74), 7.134 (0.50), 7.302 (0.99), 7.314 (0.99), 7.658(0.87), 7.662 (0.55), 7.677 (0.68), 7.699 (0.70), 8.138 (0.47), 8.150(0.52), 8.217 (1.47), 8.229 (1.40), 8.287 (0.68), 8.394 (2.17), 13.689(0.48), 14.737 (1.26). LC-MS (method 2): R_(t) = 1.18 min; MS (ESIpos):m/z = 503 [M + H]⁺ 6-58

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.024 (2.52), 1.042 (5.39), 1.059(2.57), 1.251 (16.00), 2.518 (1.53), 2.522 (1.04), 2.745 (0.64), 2.762(1.26), 2.779 (0.75), 3.137 (0.46), 3.144 (0.54), 3.154 (0.84), 3.160(0.79), 3.411 (0.80), 3.428 (2.66), 3.445 (2.49), 3.463 (0.75), 3.780(6.63), 3.782 (6.81), 3.826 (1.18), 4.034 (4.32), 4.685 (1.42), 4.699(1.40), 7.049 (0.68), 7.065 (0.82), 7.068 (1.40), 7.074 (0.88), 7.084(0.73), 7.096 (0.77), 7.101 (0.75), 7.285 (1.19), 7.297 (1.19), 7.651N-(3-fluoro-2- methoxyphenyl)-4- hydroxy-2-oxo- 1.2.5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-7, 200 mg, 675μmol) 1-[3-(2-ethoxy-2- methylpropoxy)pyridin- 4-yl]methanamine(intermediate 2-58, 151 mg, 675 μmol) 4-({[3-(2-ethoxy-2- (0.79), 7.656(0.51), methylpropoxy)pyridin-4- 7.668 (0.64), 7.710yl]methyl}amino)-N-(3-fluoro-2- (0.84), 8.231 (1.80),methoxyphenyl)-2-oxo-1,2,5,6- 8.243 (1.76), 8.400 tetrahydropyridine-3-(2.81), 13.692 carbothioamide (0.57), 14.737 (1.49). LC-MS (method 2):R_(t) = 1.21 min; MS (ESIpos): m/z = 503 [M + H]⁺ 6-59

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.216 (0.53), 1.231 (16.00), 2.075(0.89), 2.518 (1.91), 2.523 (1.39), 2.752 (0.58), 2.769 (1.18), 2.785(0.67), 3.141 (0.45), 3.149 (0.50), 3.159 (0.81), 3.165 (0.75), 3.174(0.44), 3.715 (12.53), 3.902 (4.27), 4.690 (3.06), 4.739 (1.36), 4.754(1.34), 7.091 (0.90), 7.112 (1.90), 7.132 (1.10), 7.276 (1.13), 7.287(2.37), 7.291 (1.55), 7.308 (1.02), 7.311 (0.96), 7.737 (0.81), 7.796N-(3-chloro-2- methoxyphenyl)-4- hydroxy-2-oxo- 1,2,5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-32, 166 mg. 96%purity, 510 μmol)1-{[4- (aminomethyl)pyridin- 3-yl]oxy}-2-methylpropan-2-ol (intermediate 2-1), 91.0 mg, 464 μmol)N-(3-chloro-2-methoxyphenyl)- (0.91), 7.799 (0.91), 4-({[3-(2-hydroxy-2-7.816 (0.88), 7.820 methylpropoxy)pyridin-4- (0.81), 8.224 (1.82),yl]methyl}amino)-2-oxo-1,2,5,6- 8.236 (1.64), 8.353tetrahydropyridine-3- (2.67), 13.701 carbothioamide (0.57), 14.793(1.50). LC-MS (method 2): R_(t) = 1.07 min; MS (ESIpos): m/z = 492 [M +H]⁺ 6-60

LC-MS (method 2): R, = 1.21 min; MS (ESIpos): m/z = 503 [M + H]⁺N-(3-chloro-2- methylphenyl)-4- hydroxy-2-oxo- 1,2,5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-36, 408 mg, 1.37mmol) 1-{[4-(aminomethyl) pyridin-3-yl]oxy}-N,N, 2-trimethylpropan-2-amine (intermediate 2-60), 399 mg, 1.79 mmol)N-(3-chloro-2-methylphenyl)-4- [({3-[2-(dimethylamino)-2-methylpropoxy]pyridin-4- yl}methyhamino]-2-oxo-1,2,5,6-tetrahydropyridine-3- carbothioamide 6-61

LC-MS (method 2): R_(t) = 1.13 min; MS (ESIpos): m/z = 486 [M + H]⁺N-(3-fluoro-2- methylphenyl)-4- hydroxy-2-oxo- 1.2.5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-9), 250 mg. 892μmol) 1-{[(4-(aminomethyl) pyridin-3-yl]oxy}-N,N, 2-trimethylpropan-2-amine (intermediate 2-60), 199 mg, 892 μmol)4-[({3-[2-(dimethylamino)-2- methylpropoxy]pyridin-4-yl}methyhamino]-N-(3-fluoro-2- methylphenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3- carbothioamide 6-62

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.107 (13.91), 2.010 (3.00), 2.222(16.00), 2.518 (0.45), 2.772 (0.54), 2.789 (1.10), 2.806 (0.63), 3.146(0.42), 3.153 (0.49), 3.163 (0.77), 3.170 (0.74), 3.179 (0.42), 4.006(3.59), 4.680 (1.25), 4.695 (1.24), 7.100 (0.69), 7.108 (0.57), 7.117(0.49), 7.124 (0.44), 7.133 (0.52), 7.274 (1.02), 7.286 (1.03), 7.747(0.74), 8.224 (1.48), 8.235 (1.43), 8.404 (2.33), 13.607 (0.47), 14.679(0.93). N-(3,5-difluoro-2- methylphenyl)-4- hydroxy-2-oxo- 1.2.5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-40. 260 mg. 871μmol) 1-{[4-(aminomethyl) pyridin-3-yl]oxy}-N,N, 2-trimethylpropan-2-amine (intermediate 2-60), 253 mg, 1.13 mmol) N-(3,5-difluoro-2- LC-MS(method 1): trimethylpropan-2- R_(t) = 0.73 min; MSmethylphenyl)-4-[({3-[2- (ESIpos): m/z = 504 (dimethylamino)-2- [M + H]⁺methylpropoxy]pyridin-4- yl}methypamino]-2-oxo-1,2,5,6-tetrahydropyridine-3- carbothioamide 6-63

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.035 (1.32), 1.053 (2.16), 1.070(1.37), 1.390 (0.65), 1.465 (0.72), 1.523 (0.78), 2.023 (0.80), 2.030(1.08), 2.036 (0.66), 2.228 (6.95), 2.232 (11.51), 2.238 (2.91), 2.252(0.76), 2.518 (1.34), 2.522 (0.87), 2.743 (0.72), 2.773 (1.13), 2.791(1.19), 2.808 (0.74), 3.156 (1.00), 3.163 (0.98), 3.423 (1.51), 3.710(16.00), 4.033 (0.71), 4.045 N-(3-chloro-2- methoxyphenyl)-4-hydroxy-2-oxo- 1.2.5,6- tetrahydropyridine-3- carbothioamide(intermediate 5-32, 200 mg, 639 μmol) 1-(3-{[(2S)-1- methylpiperidin-2-yl]methoxy}pyridin-4- yl)methanamine (intermediate 2-63, 241 mg, 1.02mmol) N-(3-chloro-2-methoxyphenyl)- (0.66), 4.057 (0.77),yl]methoxy}pyridin-4- 4.070 (0.76), 4.2354-{[(3-{[(2S)-1-methylpiperidin- (0.90), 4.246 (0.91), yl)methanamine4.650 (0.88), 4.658 2-yl]methoxy}pyridin-4- (0.96), 4.664 (0.97),yl)methyl]amino}-2-oxo-1,2,5,6- 4.672 (0.87), 7.084tetrahydropyridine-3- (1.21), 7.105 (2.65), carbothioamide 7.125 (1.49),7.280 (1.51), 7.284 (1.55), 7.301 (2.72), 7.304 (1.65), 7.312 (1.48),7.723 (0.96), 7.799 (1.25), 7.803 (1.29), 7.820 (1.21), 7.823 (1.10),8.154 (0.99), 8.165 (0.99), 8.224 (2.25), 8.236 (2.28), 8.244 (1.43),8.276 (0.87), 8.293 (0.69), 8.397 (3.30), 13.658 (0.66), 14.790 (1.18).LC-MS (method 1): R_(t) = 0.85 min; MS (ESIpos): m/z = 530 [M + H]⁺ 6-64

LC-MS (method 2): R, = 1.06 min; MS (ESIpos): m/z = 510 [M + H]⁺N-[2-(difluoromethoxy)- 3-fluorophenyl]-4- hydroxy-2-oxo- 1.2,5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-8, 200 mg, 602μmol) 2-{(4-(aminomethyl) pyridin-3-yl]oxy}-N,N- dimethylethan-1- amine(CAS 1513085-25-0), 176 mg, 903 μmol) N-[2-(difluoromethoxy)-3-fluorophenyl]-4-[({3-[2- (dimethylamino)ethoxy]pyridin-4-yl}methyhamino]-2-oxo- 1,2,5,6-tetrahydropyridine-3- carbothioamide6-65

LC-MS (method 2): R_(t) = 1.08 min; MS (ESIpos): m/z = 471 [M + H]⁺N-(3-fluoro-2- methylphenyl)-4- hydroxy-2-oxo- 1,2.5.6-tetrahydropyridine-3- carbothioamide (intermediate 5-9), 250 mg, 892μmol) 1-{3-[(oxolan-3- yl)methoxy]pyridin-4- yl}methanamine(intermediate 2-65), 186 mg, 892 μmol) N-(3-fluoro-2-methylphenyl)-2-oxo-4-({[3-(tetrahydrofuran-3- ylmethoxy)pyridin-4-yl]methyl}amino)-1,2,5,6- tetrahydropyridine-3- carbothioamide 6-66

¹H-NMR (400 MHz, ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.736 (0.50), 1.743(0.44), 1.764 (0.50), 1.817 (0.44), 1.836 (0.57), 1.855 (0.69), 1.872(0.62), 1.888 (0.40), 1.980 (0.41), 2.518 (1.27), 2.523 (0.79), 2.755(0.78), 2.771 (1.58), 2.788 (0.91), 3.138 (0.60), 3.145 (0.69), 3.155(1.09), 3.161 (1.03), N-(3-chloro-2- methoxyphenyl)-4- hydroxy-2-oxo-1,2,5,6- tetrahydropyridine-3- carbothioamide (intermediate 5-32, 250mg, 90% purity, 719 μmol) 1-(3-{[(2S)-oxolan-2- yl]methoxy}pyridin-4-yl)methanamine (intermediate 2-66), 209 mg, 93% purity, 935 μmol)N-(3-chloro-2-methoxyphenyl)- 3.171 (0.59), 3.1792-oxo-4-{[(3-{[(2S)-oxolan-2- (0.49), 3.654 (0.44),yl]methoxy}pyridin-4- 3.670 (0.66), 3.674 yl)methyl]amino}-1,2,5,6-(0.81), 3.690 (0.94), tetrahydropyridine-3- 3.692 (0.88), 3.712carbothioamide (16.00), 3.761 (0.60), 3.778 (1.05), 3.794 (0.71), 3.797(0.72), 4.111 (0.50), 4.122 (1.09), 4.137 (1.63), 4.143 (1.26), 4.153(1.59), 4.179 (0.75), 4.196 (0.63), 4.206 (0.53), 4.212 (0.51), 4.655(1.83), 4.670 (1.82), 7.090 (1.14), 7.110 (2.44), 7.131 (1.40), 7.286(1.61), 7.289 (1.73), 7.296 (1.58), 7.306 (2.00), 7.309 (2.51), 7.729(1.07), 7.790 (1.17), 7.794 (1.18), 7.811 (1.12), 7.814 (1.06), 8.230(2.33), 8.241 (2.19), 8.394 (3.51), 13.686 (0.74), 14.789 (1.96). LC-MS(method 2): R_(t) = 1.14 min; MS (ESIpos): m/z = 504 [M + H]⁺ 6-67

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.735 (0.48), 1.742 (0.43), 1.763(0.49), 1.816 (0.42), 1.836 (0.56), 1.854 (0.68). 1.871 (0.60), 1.979(0.40), 2.518 (0.94), 2.522 (0.62), 2.755 (0.76), 2.771 (1.55), 2.788(0.90), 3.138 3.155 (1.05), 3.161 (1.00), 3.171 (0.57), 3.178 (0.48),3.654 (0.43), 3.669 (0.62), 3.674 (0.80), 3.690 (0.90), 3.692 (0.86),3.712 (16.00), N-(3-chloro-2- methoxyphenyl)-4- hydroxy-2-oxo- 1,2,5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-32, 250 mg, 90%purity, 719 μmol) 1-(3-{[(2R)-oxolan-2- yl]methoxy}pyridin-4-yl)methanamine (intermediate 2-67), 195 mg, 935 μmol)N-(3-chloro-2-methoxyphenyl)- 3.760 (0.59), 3.7772-oxo-4-{[(3-{[(2R)-oxolan-2- (1.05), 3.793 (0.70), (0.56), 3.145 (0.65)3.797 (0.71), 4.111 yl]methoxy}pyridin-4- (0.49), 4.121 (1.07),yl)methyl]amino}-1,2,5,6- 4.136 (1.59), 4.142 tetrahydropyridine-3-(1.21), 4.152 (1.57), carbothioamide 4.178 (0.74), 4.195 (0.62), 4.206(0.51), 4.212 (0.51), 4.655 (1.80), 4.670 (1.80), 7.090 (1.11), 7.110(2.38), 7.130 (1.37), 7.285 (1.45), 7.289 (1.56), 7.297 (1.55), 7.306(1.71), 7.309 (2.72), 7.727 (1.05), 7.789 (1.15), 7.793 (1.18), 7.810(1.11), 7.813 (1.06), 8.229 (2.33), 8.241 (2.18), 8.393 (3.52), 13.686(0.72), 14.787 (1.92). LC-MS (method 2): R_(t) = 1.14 min; MS (ESIpos):m/z = 504 [M + H]⁺ 6-68

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.467 (1.00), 1.476 (1.30), 1.482(1.39), 1.663 (0.46), 1.799 (0.44), 2.518 (1.07), 2.522 (0.72), 2.757(0.68), 2.774 (1.38), 2.791 (0.82), 3.139 (0.53), 3.147 (0.60), 3.156(0.98), 3.163 (0.95), 3.172 (0.53), 3.180 (0.45), 3.385 (0.44), 3.658(0.42), 3.713 (16.00), 3.875 (0.49), 3.879 (0.50), 3.906 (0.49), 4.098(1.36), 4.108 (2.26), 4.123 (1.20), N-(3-chloro-2- methoxyphenyl)-4-hydroxy-2-oxo- 1.2,5,6- tetrahydropyridine-3- carbothioamide(intermediate 5-32, 250 mg. 90% purity, 719 μmol) 1-(3-{[(2S)-oxan-2-yl]methoxy}pyridin-4- yl)methanamine (intermediate 2-68, 335 mg, 62%purity, 935 μmol) N-(3-chloro-2-methoxyphenyl)- 4.656 (1.53), 4.6702-oxo-4-({[3-(tetrahydro-2H- (1.58), 7.088 (1.09),pyran-2-ylmethoxy)pyridin-4- 7.109 (2.32), 7.129yl]methyl}amino)-1,2,5,6- (1.35), 7.284 (1.53), tetrahydropyridine-3-7.288 (1.66), 7.297 carbothioamide (1.46), 7.304 (1.49), 7.308 (2.57),7.726 (0.99), 7.801 (1.14), 7.804 (1.15), 7.821 (1.11), 7.825 (1.04),8.224 (2.15), 8.235 (2.03), 8.385 (3.26), 13.680 (0.67), 14.791 (1.67).LC-MS (method 2): R_(t) = 1.22 min; MS (ESIpos): m/z = 517 [M + H]⁺ 6-69

¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.851 (0.43), 1.232 (1.49), 1.282(0.86), 1.291 (0.82), 1.312 (2.31), 1.341 (2.79), 1.372 (1.78), 1.434(1.25), 1.480 (9.75), 1.511 (1.73), 1.660 (3.27), 1.691 (2.74), 1.799(3.08), 1 .812 (2.26), 1.907 (1.59), 2.074 (6.92), 2.518 (12.20), 2.523(7.83), 2.545 (0.43), 2.768 (4.76), 2.786 N-(2,3- dichlorophenyl)-4-hydroxy-2-oxo- 1.2,5,6- tetrahydropyridine-3- carbothioamide(intermediate 5-34. 200 mg, 631 μmol) 1-[3-(tetrahydro-2H- pyran-2-ylmethoxy)pyridin-4- yl]methanamine (intermediate 2-68, 154 mg, 694μmol) N-(2,3-dichlorophenyl)-2-oxo-4- (9.51), 2.802 (5.91),({[3-(tetrahydro-2H-pyran-2- 3.149 (3.75), 3.156 ylmethoxy)pyridin-4-(4.32), 3.166 (7.02), yl]methyl}amino)-1,2,5,6- 3.172 (6.73), 3.345tetrahydropyridine-3- (2.64), 3.358 (2.11), carbothioamide 3.382 (3.27),3.398 (1.83), 3.409 (2.16), 3.655 (2.98), 3.660 (2.31), 3.670 (2.45),3.682 (2.69), 3.692 (1.63), 3.698 (1.39), 3.831 (1.11), 3.876 (3.46),3.903 (3.41), 4.068 (1.87), 4.078 (2.40), 4.094 (8.79), 4.104 (16.00),4.118 (7.98), 4.129 (2.02), 4.144 (2.11), 4.657 (10.23), 4.672 (10.57),7.292 (5.43), 7.303 (5.91), 7.330 (6.87), 7.350 (15.86), 7.370 (10.23),7.497 (8.22), 7.500 (10.67), 7.517 (7.35), 7.521 (7.78), 7.531 (8.79),7.534 (7.35), 7.551 (7.21), 7.554 (6.05), 7.742 (6.82), 8.222 (4.13),8.234 (4.04), 8.385 (6.20), 13.641 (2.50), 13.656 (5.00), 13.670 (2.35),14.893 (13.89). LC-MS (method 2): R_(t) = 1.23 min; MS (ESIpos): m/z =522 [M + H]⁺ 6-70

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (0.70), 1.172 (1.12), 1.190(0.56), 1.232 (0.64), 1.691 (0.80), 1.708 (1.95), 1.712 (1.36), 1.720(1.26), 1.724 (1.47), 1.729 (2.60), 1.736 (2.41), 1.742 (1.63) 1.746(1.82), 1.753 (1.69), 1.758 (2.73 ), 1.774 (2.43), 1.789 (0.99), 1.801(1.31), N-(2,3- dichlorophenyl)-4- hydroxy-2-oxo- 1.2,5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-34. 200 mg, 631μmol) 1-(3-{[(2S)-oxolan-2- yl]methoxy}pyridin-4- yl)methanamine(intermediate 2-66), 144 mg, 694 μmol) N-(2,3-dichlorophenyl)-2-oxo-4-1.807 (1.26), 1.817 {[(3-{[(2S)-oxolan-2- (2.25), 1.825 (1.47),yl]methoxy}pyridin-4- 1.837 (3.02), 1.855 yl)methyl]amino}-1,2,5,6-(4.17), 1.862 (1.10), tetrahydropyridine-3- 1.872 (3.34), 1.887carbothioamide (2.03), 1.891 (1.79), 1.904 (1.71), 1.908 (1.55), 1.917(0.62), 1.922 (0.70), 1.938 (0.45), 1.960 (1.71), 1.974 (1.44), 1.979(2.22), 1.988 (2.54), 1.990 (2.19), 2.000 (1.77), 2.004 (1.74), 2.011(1.95), 2.022 (1.55), 2.028 (1.23), 2.040 (0.72), 2.075 (1.31), 2.518(5.99), 2.523 (4.25), 2.767 (4.07), 2.783 (8.35), 2.800 (4.82), 3.148(3.05), 3.155 (3.51), 3.165 (5.67), 3.171 (5.35), 3.181 (3.05), 3.188(2.57), 3.653 (2.35), 3.669 (3.18), 3.674 (4.33), 3.689 (5.11), 3.691(4.23), 3.706 (2.92), 3.758 (3.29), 3.775 (5.75), 3.791 (3.80), 3.795(3.88), 3.812 (2.06), 4.092 (1.90), 4.107 (2.65), 4.118 (5.81), 4.133(9.12), 4.138 (6.98), 4.148 (8.78), 4.163 (1.58), 4.173 (3.88), 4.185(1.34), 4.192 (3.37), 4.201 (2.81), 4.207 (2.76), 4.218 (2.17), 4.223(1.15), 4.233 (0.86), 4.658 (9.58), 4.672 (9.53), 7.289 (7.44), 7.301(7.65), 7.331 (5.91), 7.352 (13.73), 7.372 (8.86), 7.498 (6.66), 7.501(9.39), 7.518 (6.21), 7.522 (6.98), 7.526 (7.71), 7.529 (5.99), 7.546(5.99), 7.549 (4.90), 7.744 (5.59), 8.225 (10.17), 8.236 (9.63), 8.392(16.00), 13.645 (2.09), 13.659 (4.12), 13.675 (1.90), 14.892 (11.45).LC-MS (method 2): R_(t) = 1.15 min; MS (ESIpos): m/z = 508 [M + H]⁺ 6-71

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.638 (0.44), 1.654 (1.19), 1.670(1.38), 1.679 (1.33), 1.689 (0.96), 1.702 (0.73), 1.709 (0.46), 1.952(0.45), 1.961 (0.44), 1.972 (0.53), 1.987 (0.53), 2.159 (0.46), 2.181(1.18), 2.202 (0.96), 2.355 (16.00), 2.518 (2.15), 2.523 (1.42), 2.604(0.44), 2.610 (0.40), 2.618 (0.49), N-(2,3- dichlorophenyl)-4-hydroxy-2-oxo- 1,2,5,6- tetrahydropyridine-3- carbothioamide(intermediate 5-34, 200 mg. 631 μmol) 1-(3-{[(2S)-1- methylpyrrolidin-2-yl]methoxy}pyridin-4- yl)methanamine (intermediate 2-4, 153 mg, 694μmol) N-(2,3-dichlorophenyl)-4-{[(3- 2.625 (0.61), 2.639{[(2S)-1-methylpyrrolidin-2- (0.51), 2.756 (0.80), yl]methoxy}pyridin-4-2.774 (1.65), 2.790 yl)methyl]amino}-2-oxo-1,2,5,6- (1.03), 2.936(0.42), tetrahydropyridine-3- 2.945 (0.50), 2.950 carbothioamide (0.69),2.961 (0.47), 2.967 (0.47), 3.146 (0.68), 3.154 (0.78), 3.163 (1.28),3.169 (1.24), 3.969 (0.81), 3.983 (0.85), 3.993 (1.03), 4.007 (1.00),4.142 (1.03), 4.155 (1.09), 4.166 (0.87), 4.179 (0.81), 4.648 (1.88),4.663 (1.89), 7.287 (1.53), 7.299 (1.58), 7.330 (1.36), 7.350 (3.03),7.371 (1.95), 7.496 (1.47), 7.500 (2.10), 7.516 (1.34), 7.520 (1.51),7.526 (1.72), 7.530 (1.40), 7.546 (1.35), 7.549 (1.11), 7.741 (1.21),8.220 (2.08), 8.231 (1.99), 8.390 (3.32), 13.632 (0.43), 13.646 (0.88),13.661 (0.43), 14.887 (2.34). LC-MS (method 2): R_(t) = 1.19 min; MS(ESIpos): m/z = 521 [M + H]⁺ 6-72

LC-MS (method 2): R_(t) = 1.02 min; MS (ESIpos): m/z = 475 [M + H]⁺N-(3-fluoro-2- methoxyphenyl)-4- hydroxy-2-oxo- 1.2,5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-7). 200 mg. 675μmol) 1-{[4-(aminomethyl) pyridin-3-yl]oxy}-2- methylpropan-2-ol(intermediate 2-1), 199 mg, 1.01 mmol) N-(3-fluoro-2-methoxyphenyl)-4-({[3-(2-hydroxy-2- methylpropoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6- tetrahydropyridine-3- carbothioamide6-73

LC-MS (method 2): R_(t) = 1.04 min; MS (ESIpos): m/z = 510 [M + H]⁺N-[2- (difluoromethoxy)-3- fluorophenyl]-4- hydroxy-2-oxo- 1.2.5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-8, 200 mg, 602μmol) (aminomethyl)pyridin- 3-yl]oxy}-2- methylpropan-2-ol (intermediate2-1), 177 mg, 903 μmol) N-[2-(difluoromethoxy)-3-fluorophenyl]-4-({[3-(2-hydroxy- 2-methylpropoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6- tetrahydropyridine-3- carbothioamide6-74

LC-MS (method 2): R_(t) = 1.04 min; MS (ESIpos): m/z = 502 [M + H]⁺N-(3-fluoro-2- methoxyphenyl)-4- hydroxy-2-oxo- 1.2,5,6-tetrahydropyridine-3- carbothioamide (intermdiate 5-7), 200 mg, 675μmol) 1-{[4- (aminomethyl)pyridin- 3-yl]oxy}-N,N,2- trimethylpropan-2-amine (intermediate 2-60), 226 mg, 1.01 mmol)4-[({3-[2-(dimethylamino)-2- methylpropoxy]pyridin-4-yl}methyhamino]-N-(3-fluoro-2- methoxyphenyl)-2-oxo-1,2,5,6-tetrahydropyridine-3- carbothioamide 6-75

LC-MS (method 2): R_(t) = 1.10 min; MS (ESIpos): m/z = 544 [M + H]⁺N-(3-fluoro-2- methoxyphenyl)-4- hydroxy-2-oxo- 1.2,5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-7), 200 mg, 675μmol) 1-{3-[2-methyl-2- (morpholin-4- yl)propoxy]pyridin-4-yl}methanamine (intermediate 2-3), 269 mg, 1.01 mmol)N-(3-fluoro-2-methoxyphenyl)- 4-[({3-[2-methyl-2-(morpholin-4-yl)propoxy]pyridin-4- yl}methyhamino]-2-oxo-1,2,5,6-tetrahydropyridine-3- carbothioamide 6-76

LC-MS (method 2): R_(t) = 1.14 min; MS (ESIpos): m/z = 580 [M + H]⁺N-[2- (difluoromethoxy)-3- fluorophenyl]-4- hydroxy-2-oxo- 1,2,5,6-tetrahydropyridine-3- carbothioamide (intermediate 5- 8,200 mg, 602μmol) 1-{3-[2-methyl-2- (morpholin-4- yl)propoxy]pyridin-4-yl}methanamine (intermediate 2-3) 269 mg, 1.01 mmol)N-[2-(difluoromethoxy)-3- fluorophenyl]-4-[({3-[2-methyl-2-(morpholin-4- yl)propoxy]pyridin-4- yl}methyhamino]-2-oxo-1,2,5,6-tetrahydropyridine-3- carbothioamide 6-77

¹H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.654 (1.52), 1.670 (1.83), 1.679(1.64), 1.684 (1.08), 1.689 (1.27), 1.702 (0.92), 1.971 (0.70), 2.075(0.98), 2.157 (14.18), 2.183 (1.09), 2.204 (0.96), 2.357 (16.00), 2.518(1.07), 2.523 (0.70), 2.627 (0.69), 2.735 (1.06), 2.752 (2.13), 2.769(1.34), 2.947 (0.64), 2.953 (0.85), 3.142 (0.92), 3.150 (1.06), 3.159N-(3-chloro-2- methylphenyl)-4- hydroxy-2-oxo- 1,2,5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-36, 461 mg, 1.55mmol) 1-(3-{[(2S)-1- methylpyrrolidin-2- yl]methoxy}pyridin-4-yl)methanamine (intermediate 2-4, 447 mg, 2.02 mmol)N-(3-chloro-2-methylphenyl)-4- (1.73), 3.166 (1.68),{[(3-{[(2S)-1-methylpyrrolidin-2- 3.175 (0.93), 3.183yl]methoxy}pyridin-4- (0.79), 3.965 (0.96),yl)methyl]amino}-2-oxo-1,2,5,6- 3.980 (1.02), 3.989tetrahydropyridine-3- (1.24), 4.004 (1.17), carbothioamide 4.140 (1.38),4.153 (1.42), 4.164 (1.12), 4.176 (1.06), 4.627 (2.69), 4.642 (2.71),7.148 (1.18), 7.165 (2.18), 7.168 (2.08), 7.198 (1.52), 7.218 (2.45),7.238 (1.10), 7.284 (2.28), 7.296 (2.33), 7.325 (1.96), 7.328 (1.99),7.345 (1.50), 7.348 (1.40), 7.684 (1.59), 8.217 (3.30), 8.229 (3.13),8.385 (5.13), 13.625 (0.98), 14.533 (2.35). LC-MS (method 2): R_(t) =1.19 min; MS (ESIpos): m/z = 501 [M + H]⁺ 6-78

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.172 (0.49), 1.227 (3.01), 1.233(4.64), 1.238 (16.00), 1.917 (1.09), 1.988 (0.67), 2.618 (2.76), 2.522(1.75), 2.767 (0.47), 2.783 (0.97), 2.800 (0.59), 3.150 (0.78), 3.155(1.53), 3.167 (13.22), 3.175 (1.72), 3.180 (2.87), 3.185 (1.48), 3.188(1.47), 3.988 (0.94), 3.999 (0.63), 4.033 (3.79), 4.688 (1.15), 4.703(1.15), 5.651 (0.41), 6.710 N-(2-bromo-3- chlorophenyl)-4-hydroxy-2-oxo- 1,2,5,6- tetrahydropyridine-3- carbothioamide(intermediate 5-78), 350 mg. 968 μmol) 1-[3-(2-methoxy-2-methylpropoxy)pyridin- 4-yl]methanamine (intermediate 2-2), 265 mg, 1.26mmol) N-(2-bromo-3-chlorophenyl)-4- (0.47), 6.717 (0.47),({[3-(2-methoxy-2- 6.730 (0.58), 6.736 methylpropoxy)pyridin-4- (0.56),7.041 (0.62), yl]methyl}amino)-2-oxo-1,2,5,6- 7.277 (0.97), 7.289tetrahydropyridine-3- (1.08), 7.363 (0.49), carbothioamide 7.383 (1.31),7.402 (1.32), 7.423 (0.84), 7.427 (1.17), 7.442 (0.57), 7.447 (0.41),7.482 (1.04), 7.487 (0.91), 7.501 (0.73), 7.506 (0.63), 7.732 (0.67),8.229 (1.59), 8.241 (1.44), 8.290 (0.42), 8.397 (2.35), 13.658 (0.50),14.851 (1.29). LC-MS (method 2): R_(t) = 1.20 min; MS (ESIpos): m/z =554 [M + H]⁺ 6-79

¹H NMR (400 MHz, DMSO): d [ppm] = 1.64-1.76 (m, 1H), 1.96-2.09 (m, 1H),2.65-2.84 (m, 3H), 3.11-3.22 (m, 2H), 3.55-3.70 (m. 2H), 3.72-3.85 (m,2H), 4.02-4.20 (m, 2H), 4.66 (d, 2H), 6.91 (t, 1H), 7.27-7.37 (m, 2H),7.46 (d, 1H), 7.60 (d, 1H), 7.72 (br s, 1H), 8.24 (d, 1H), 8.40 (s, 1H),13.62 (br s, 1H), 14.79 (br s, 1H), 19F NMR (400 MHz, DMSO): dN-[3-chloro-2- (difluoromethoxy)phenyl]- 4-hydroxy-2-oxo- 1.2,5,6-tetrahydropyridine-3- carbothioamide (intermediate 5- 38),402 mg, 1.15mmol) 1-{3-[(oxolan-3- yl)methoxy]pyridin-4- yl}methanamine(intermediate 2-65), 480 mg, 2.30 mmol) N-[3-chloro-2- [ppm] = −80.12(d), (difluoromethoxy)phenyl]-2- UPLC4-MS oxo-4-({[3-(tetrahydrofuran-3-(Method 3): R_(t) = ylmethoxy)pyridin-4- 1.46 min, 95%., MSyl]methyl}amino)-1,2,5,6- (ESIpos): m/z = tetrahydropyridine-3- (M + H)+= 539 carbothioamide 6-80

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (0.60), 1.172 (1.23), 1.190(0.62), 1.232 (0.48), 1.379 (7.74), 1.393 (9.81), 1.417 (1.01), 1.789(0.58), 1.798 (0.60), 1.807 (0.60), 1.815 (0.52), 1.820 (0.40), 1.907(0.56), 1.917 (0.68), 1.921 (0.78), 1.927 (0.94), 1.936 (0.88), 1.941(1.17), 1.948 (1.17), 1.955 (1.21), 1.987 (2.69), 2.336 (0.44), 2.518(5.63), 2.522 (3.62), 2.678 (0.42), 2.752 (0.70), 2.768 (0.86), 3.053(0.52), 3.141 (0.54), 3.148 (0.64), 3.157 (1.05), 3.164 (1.05), 3.181(0.52), 3.280 (1.51), 3.294 N-(3-chloro-2- methoxyphenyl)-4-hydroxy-2-oxo- 1.2,5,6- tetrahydropyridine-3- carbothioamide(intermediate 5-32), 400 mg, 90% purity, 1.15 mmol) tert-butyl(2S)-2-({(4- (aminomethyl)pyridin-3- yl]oxy}methyl)pyrrolidine-1-carboxylate (intermediate 2-80), 460 mg, 1.50 mmol) (1.17), 3.425(0.78), 3.669 (16.00), 3.710 (10.87), 3.806 (0.40), 3.813 (0.46), 4.017(0.56), 4.035 (0.82), 4.053 (0.84), 4.071 (1.01), 4.135 (0.58), 4.143(0.54), 4.157 (0.66), 4.166 (0.64), 4.225 (0.54), 4.420 (0.66), 4.440(0.74), 4.442 (0.72), 4.462 (0.54), 4.654 (1.19), 4.669 (1.23), 5.232(1.45), 6.526 (1.19), 6.530 (1.33), 6.546 (1.43), 6.550 (1.53), 6.608(1.19), 6.612 (1.17), 6.628 (1.61), 6.632 (1.39), 6.768 (1.41), 6.788(2.29), 6.808 (0.96), 7.084 (1.01), 7.105 (2.29), 7.125 (1.27), 7.284(1.47), 7.288 (1.69), 7.304 (1.83), 7.308 (1.75), 7.733 (0.96), 7.794(1.05), 7.797 (1.09), 7.814 (1.01), 7.817 (0.98), 8.234 (0.94), 8.246(0.96), 8.426 (2.65), 13.691 (0.50), 14.787 (1.81). LC-MS (method 1):R_(t) = 1.29 min; MS (ESIpos): m/z = 603 [M + H]⁺ 6-81

¹H NMR (400 MHz, CDCl3): d [ppm] = 2.54-2.65 (m, 4H), 2.70-2.76 (m, 2H),2.80-2.90 (m, 4H), 3.32-3.39 (m, 2H), 3.68-3.80 (m, 4H), 4.20-4.35 (m,2H), 5.92-5.99 (m, 1H), 6.30-6.75 (m, 1H), 7.20-7.26 (m, 2H), 7.35 (d,1H), 7.65 (d, 1H), 8.20-8.34 (m, 2H), 14.4 (br s, 1H), 14.30 (br s, 1H)19F NMR (400 MHz, CDCl₃): d [ppm] = 80.4 (d), UPLC-MS (Method 3): R_(t)= 1.25 min, 69%., MS (ESIpos): m/z = (M + H)+ = 568 N-[3-chloro-2-(difluoromethoxy)phe nyl]-4-hydroxy-2-oxo- 1.2,5,6-tetrahydropyridine-3- carbothioamide (intermediate 5-38), 525 mg, 1.50mmol) 1-{3-[2-(morpholin-4- yl)ethoxy]pyridin-4- yl}methanamine(intermediate 2-81), 714 mg, 3.01 mmol) N-[3-chloro-2-(difluoromethoxy)phenyl]-4-[({3- [2-(morpholin-4- yl)ethoxy]pyridin-4-yl}methyhamino]-2-oxo-1,2,5,6- tetrahydropyridine-3- carbothioamide 6-96

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.035 (0.45), 1.052 (0.99), 1.070(0.46), 1.335 (4.63), 1.363 (2.71), 1.381 (5.04), 1.417 (3.82), 2.518(1.40), 2.522 (0.88), 2.734 (0.88), 2.751 (1.72), 2.767 (0.98), 2.875(2.11), 2.891 (2.00), 3.144 (0.78), 3.154 (1.23), 3.160 (1.19), 3.575(1.08), 3.588 (2.03), 3.601 (1.06), 3.750 (16.00), 3.763 (0.51), 4.268(0.95), 4.636 (1.76), 4.651 (1.78), 7.173 (1.20), 7.195 (2.21), 7.218(1.23), 7.298 (0.63), 7.681 (0.71), 7.696 (0.78), 7.704 (0.74), 7.719(0.70), 7.743 (1.17), 8.234 (1.29), 8.245 (1.26), 8.396 (0.55), 8.419(0.83), 13.677 (0.46), 14.707 (1.63), N-(3-chloro-4-fluoro-2-methoxyphenyl)-4- hydroxy-2-oxo- 1.2,5,6- tetrahydropyridine-3-carbothioamide (intermediate 5-44, 150 mg, 453 μmol) tert-butyl (2-{[4-(aminomethyl)pyridin-3- yl]oxy}ethyl) methylcarbamate (intermediate2-96), 204 mg, 726 μmol) tert-butyl [2-({4-[({5-[(3-chloro- LC-MS(method 1): 4-fluoro-2- R_(t) = 1.24 min; MSmethoxyphenyl)carbamothioyl]- (ESIneg): m/z = 5926-oxo-1,2,3,6-tetrahydropyridin- [M − H]⁻ 4-yl}amino)methyl]pyridin-3-yl}oxy)ethyl]methylcarbamate

Intermediate 6-82N-[3-chloro-2-(difluoromethoxy)phenyl]-2-oxo-4-({[3-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-4-yl]methyl}amino)-1,2,5,6-tetrahydropyridine-3-carbothioamide

A mixture ofN-[3-chloro-2-(difluoromethoxy)phenyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide,384 mg (1.10 mmol, intermediate 5-38), and1-[3-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-4-yl]methanamine, 490 mg(2.20 mmol, intermediate 2-82), mixed in dichloromethane and was heatedat 120° C. in a pre-heated bath for 90 minutes. Cooled to roomtemperature then sonicated in methanol for 45 minutes gave the product,259 mg (43%).

¹H NMR (400 MHz, DMSO-d6): δ [ppm]=1.29-1.45 (m, 2H), 1.65-1.79 (m, 2H),2.44-2.63 (m, 2H), 2.71-2.83 (, 2H), 3.11-3.22 (m, 2H), 3.3-3.39 (m,2H), 3.83-3.93 (m, 2H), 4.03 (d, 2H), 4.67 (d, 2H), 6.92 (t, 1H),7.27-7.37 (m, 2H), 7.46 (d, 1H), 7.60 (d, 1H), 7.12 (br s, 1H), 8.22 (d,1H), 8.37 (s, 1H);

UPLC4-MS (Method 3): R_(t)=1.48 min, 69%., MS (ESIpos): m/z=(M+H)⁺=553.

Intermediate 6-84N-(3-fluoro-2-methoxyphenyl)-4-(((3-hydroxypyridin-4-yl)methyl)amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

A mixture of 4-(aminomethyl)pyridin-3-ol (CAS: 20485-35-2, 75 g, 0.604mol) andN-(3-fluoro-2-methoxy-phenyl)-4-hydroxy-6-oxo-2,3-dihydro-1H-pyridine-5-carbothioamide(intermediate 5-7, 150 g, 0.506 mol) in DMA (1.2 L) was stirred at 120°C. for 2.5 h under nitrogen. The mixture was concentrated in vacuum toremove most of solvent. The dark brown solution was slowly added toEtOAc (8 L) with stirring. The resulting mixture was washed with water(2.5 L) and brine (2.5 L×2). The organic phase was dried over Na₂SO₄,filtered and concentrated in vacuum. The residue was slurried with EtOAc(300 ml.) and filtered. The cake was dried in vacuum to afford the titlecompound (87 g, 47% yield) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆): δ=14.73 (s, 1H), 13.69 (t, 1H), 10.28 (s,1H), 8.21-8.13 (m, 2H), 7.67-7.66 (m, 2H), 7.10 (br.s, 1H), 7.09-7.04(m, 2H), 4.61 (d, 2H), 3.79 (s, 3H), 3.16 (t, 2H), 2.77 (t, 2H).

Intermediate 6-87N-(3-chloro-2-methoxyphenyl)-4-{[(3-hydroxypyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide

N-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide(intermediate 5-32, 1.14 g, 3.64 mmol) and 4-(aminomethyl)pyridin-3-ol(CAS: 20485-35-2, 587 mg, 4.73 mmol) were given together, mixed well andthan heated up to 120° C. for 1 h. Substrates did not melt. DMSO (4.0ml) was added and the mixture stirred at 100° C. for 1 h. The productwas concentrated and used in the next step without any furtherpurification.

Intermediate 7-243-{[3-fluoro-2-(prop-2-en-1-yloxy)phenyl]amino}-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 6; Intermediate 6-24(190 mg, 369 μmol) as the starting material, the title compound wasprepared (77 mg, 41% yield) after concentration of the reaction mixtureand crystallization of the residue.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.15 (s, 1H), 8.41 (s, 1H), 7.98 (d,1H), 7.55 (s, 1H), 7.23 (d, 1H), 7.19-7.22 (m, 1H), 6.66 (m, 1H), 6.51(m, 1H), 6.16-6.26 (m, 1H), 6.03 (d, 1H), 5.44 (dq, 1H), 5.24-5.28 (m,1H), 4.64 (d, 2H), 4.19 (s, 2H), 3.43 (m, 2H), 3.25 (s, 3H), 2.84 (t,2H), 1.28 (s, 6H).

Intermediate 84-13-((3-fluoro-2-methoxyphenyl)amino)-2-(3-hydroxypyridin-4-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

To a suspension ofN-(3-fluoro-2-methoxy-phenyl)-4-[(3-hydroxy-4-pyridyl)methylamino]-6-oxo-2,3-dihydro-1H-pyridine-5-carbothioamide(intermediate 6-84, 41 g, 101.88 mmol) in MeOH (410 mL) was added TFA(0.75 mL, 10.13 mmol), followed by hydrogen peroxide (18 mL, 30% inwater). The mixture was heated to 60° C. and stirred for 16 h.Additional TFA (6.8 mL, 91.84 mmol) and hydrogen peroxide (1.5 mL, 30%in water) were added. The suspension was stirred at 60° C. for further 3h. The mixture was cooled to room temperature and stand overnight. Thesuspension was combined with a second batch that was generatedidentically. The combined suspension was filtered and the cake waswashed with water (250 mL) and MeOH (150 mL), and then slurried in MeOH(150 mL). The suspension was filtered. The cake was washed with MeOH (75mL) and dried in vacuum to afford the title compound (25.4 g, 33.8%) asa yellow solid.

¹H NMR (400 MHz, DMSO-d₆): δ=11.45 (s, 1H), 8.18 (s, 1H), 7.98 (d, 1H),7.39 (d, 1H), 7.18 (s, 1H), 6.67 (t, 1H), 6.54 (t, 1H), 6.04 (d, 1H),3.92 (s, 3H), 3.40 (t, 2H), 2.90 (t, 2H).

LC-MS (method 5): R_(t)=1.851 min; m/z=369.0 (M+H)⁺.

Intermediate 87-13-(3-chloro-2-methoxyanilino)-2-(3-hydroxypyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

N-(3-chloro-2-methoxyphenyl)-4-{[(3-hydroxypyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide(intermediate 6-87, 1.50 g, 3.58 mmol) was solved in methanol andtreated with TFA (280 μl, 3.6 mmol). After addition of hydrogen peroxide(220 μl, 7.2 mmol) the reaction mixture was heated to 50° C. and stirredovernight. The reaction mixture was quenched with saturated sodiumthiosulfate solution and stirred for 2 h. TEA (1.0 ml, 7.5 mmol) wasadded and the mixture was diluted with water and extracted with DCM. Thecombined organic layers were dried by hydrophobic filter paper andconcentrated under reduced pressure. The mixture was purified by prep.HPLC (basic) to give the title compound (95.7 mg, 90% purity, 6% yield)brown solid.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (5.69), 2.523 (3.86), 2.843(1.31), 2.859 (2.82), 2.876 (1.49), 3.370 (1.01), 3.376 (1.08), 3.387(1.97), 3.393 (1.91), 3.404 (0.96), 3.410 (0.86), 3.700 (1.23), 3.757(0.91), 3.865 (16.00), 3.882 (0.55), 6.174 (1.79), 6.179 (1.74), 6.192(1.86), 6.198 (1.79), 6.653 (0.78), 6.667 (2.75), 6.673 (4.08), 6.691(1.71), 6.711 (0.53), 7.072 (1.71), 7.241 (1.54), 7.254 (1.54), 7.430(2.32), 7.864 (0.91), 7.877 (0.86), 8.192 (1.39), 10.461 (1.16), 11.279(1.08).

LC-MS (method 2): R, =0.59 min; MS (ESIpos): m/z=385 [M+H]⁺

Intermediate 95-1 tert-butyl(2S)-2-[({4-[3-(3-chloro-2-methoxyanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)methyl]pyrrolidine-1-carboxylate

To a solution of tert-butyl(2S)-2-[({4-[({5-[(3-chloro-2-methoxyphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)methyl]pyrrolidine-1-carboxylate(intermediate 6-80, 507 mg, 76% purity, 640 μmol) in 6.0 ml. methanolwas added TFA (99 μl, 1.3 mmol) and stirred for 5 min at rt. Thenmeta-chloroperoxybenzoic acid (221 mg, 1.28 mmol) was added and themixture was heated 1 h at 50° C. The reaction mixture was cooled down tort and quenched with an aqueous saturated sodium thiosulfate solutionand stirred for 30 min at rt. Triethylamine (190 μl, 1.3 mmol) and waterwas added and the mixture was extracted with dichloromethane two timesThe combined organic layers were filtered through a hydrophobic filterpaper and the filtrate was concentrated under reduced pressure. Theresidue was purified by flash chromatography and then by preparativeHPLC to give 9 mg of the title compound (90% purity, 2% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (4.77), 1.172 (9.54), 1.190(4.64), 1.232 (1.54), 1.406 (14.27), 1.824 (1.22), 1.988 (16.00), 2.332(1.34), 2.336 (0.61), 2.518 (8.22), 2.523 (5.18), 2.673 (1.41), 2.678(0.64), 2.841 (0.42), 2.932 (1.41), 3.413 (2.46), 3.762 (0.61), 3.883(4.86), 4.000 (1.31), 4.017 (3.81), 4.035 (4.06), 4.053 (2.34), 4.068(1.95), 4.086 (0.64), 4.331 (1.41), 6.107 (1.28), 6.119 (2.11), 6.131(1.38), 6.673 (2.05), 7.151 (1.06), 7.349 (1.31), 7.486 (1.31), 7.998(0.99), 8.417 (2.18), 11.433 (0.90).

LC-MS (method 2): R_(t)=1.29 min; MS (ESIpos): m/z=569 [M+H]⁺

Intermediate 96-1 tert-butyl[2-({4-[3-(3-chloro-4-fluoro-2-methoxyanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)ethyl]methylcarbamate

To a solution of tert-butyl[2-({4-[({5-[(3-chloro-4-fluoro-2-methoxyphenyl)carbamothioyl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}amino)methyl]pyridin-3-yl}oxy)ethyl]methylcarbamate(intermediate 6-96), 129 mg, 217 μmol) in 2.2 ml. methanol were addedTFA (17 μl, 220 μmol) and hydrogen peroxide (38 μl, 35% purity, 430μmol) and the mixture was heated 20 h at 50° C. The reaction mixture wasconcentrated under reduced pressure and the residue was purified bypreparative HPLC to give 67 mg of the title compound (90% purity, 50%yield).

LC-MS (method 2): R, =1.22 min; MS (ESIneg): m/z=558 [M−H]⁻

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.232 (0.51), 1.287 (1.02), 1.369(16.00), 2.075 (1.77), 2.518 (4.72), 2.523 (3.27), 2.540 (9.93), 2.674(0.97), 2.776 (0.55), 2.895 (2.87), 2.952 (1.19), 3.392 (1.63), 3.404(2.65), 3.420 (1.43), 3.719 (1.21), 3.803 (0.42), 3.922 (4.66), 4.316(1.57), 6.065 (0.86), 6.078 (1.04), 6.086 (1.10), 6.100 (0.93), 6.779(0.77), 7.167 (0.82), 7.355 (0.99), 7.411 (0.90), 8.013 (0.97), 8.395(5.58), 11.175 (3.38).

Intermediate 96-23-(3-chloro-4-fluoro-2-methoxyanilino)-2-{3-[2-(methylamino)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Intermediate 5-32, tert-butyl[2-({4-[3-(3-chloro-4-fluoro-2-methoxyanilino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl}oxy)ethyl]methylcarbamate(intermediate 96-1, 67.0 mg, 120 μmol) as the starting material, thetitle compound was prepared 14 mg (90% purity, 19% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.850 (0.47), 1.154 (0.67), 1.172(1.23), 1.190 (0.78), 1.230 (1.93), 1.262 (0.65), 1.369 (16.00), 1.751(1.19), 2.074 (4.82), 2.326 (0.69), 2.442 (0.52), 2.539 (4.65), 2.669(0.75), 2.894 (3.01), 2.952 (1.53), 3.082 (0.51), 3.100 (0.48), 3.404(2.97), 3.719 (1.66), 3.922 (4.70), 4.314 (1.63), 6.066 (0.81), 6.087(1.13), 6.101 (0.94), 6.779 (0.81), 7.042 (0.48), 7.063 (0.71), 7.091(0.41), 7.164 (1.21), 7.214 (0.50), 7.236 (0.85), 7.258 (0.66), 7.291(0.50), 7.355 (0.98), 7.416 (0.88), 7.796 (0.52), 8.014 (0.84), 8.133(5.43), 8.396 (2.02), 8.478 (0.47), 8.537 (0.67), 11.176 (2.95).

LC-MS (method 1): R_(t)=0.70 min; MS (ESIpos): m/z=460 [M+H]⁺

SYNTHESES OF EXAMPLES Example 12-[3-(2-methoxyethoxy)pyridin-4-yl]-3-(phenylamino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

To a solution of4-({[3-(2-methoxyethoxy)pyridin-4-yl]methyl}amino)-2-oxo-N-phenyl-1,2,5,6-tetrahydropyridine-3-carbothioamide(Intermediate 6-1; 95.1 mg, 231 μmol) in MeOH (4 ml) was added aqueoushydrogen peroxide (42 μl, 34% purity, 460 μmol) and heated at 90° C. for16 h. The reaction mixture was concentrated and was purified bypreparative HPLC (basic method) to give the title compound 33.0 mg (34%yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.97 (s, 1H), 8.37 (s, 1H), 7.97 (d,1H), 7.39-7.46 (m, 1H), 7.32 (d, 1H), 7.11 (s, 1H), 7.00 (t, 2H),6.54-6.62 (m, 3H), 4.25-4.35 (m, 2H), 3.76-3.81 (m, 2H), 3.37-3.45 (m,5H), 2.85 (t, 2H).

Example 22-[3-(3,3-dimethylbutoxy)pyridin-4-yl]-3-[(3-fluorophenyl)amino]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 1; Intermediate 6-2(173 mg, 379 μmol) as the starting material and heated for 2 h, thetitle compound was prepared 38.0 mg (21% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.15 (s, 1H), 8.36 (s, 1H), 8.04 (d,1H), 7.56 (s, 1H), 7.29 (d, 1H), 7.03 (s, 1H), 6.95 (m, 1H), 6.38 (d,1H), 6.29 (t, 1H), 6.18 (dt, 1H), 4.10 (t, 2H), 3.34-3.41 (m, 2H), 2.82(t, 2H), 2.52-2.54 (m, 1H), 1.65-1.73 (m, 2H), 0.92 (s, 9H).

Example 32-[3-(benzyloxy)pyridin-4-yl]-3-[(3-fluorophenyl)amino]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 1; Intermediate 6-3(188 mg, 406 μmol) as the starting material and heated for 2 h, thetitle compound was prepared 48.0 mg (26% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.27 (s, 1H), 8.38-8.43 (m, 1H),8.33 (s, 1H), 8.01 (d, 1H), 7.51-7.59 (m, 1H), 7.28-7.49 (m, 7H), 7.05(s, 1H), 6.93-7.02 (m, 1H), 6.35 (d, 1H), 6.31 (t, 1H), 6.21 (dt, 1H),5.33 (s, 2H), 3.35-3.43 (m, 2H), 2.84 (t, 2H).

Example 43-[(3-fluorophenyl)amino]-2-[3-(2-hydroxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 1; Intermediate 6-4(156 mg, 351 μmol) as the starting material and heated for 2 h, thetitle compound was prepared 46.0 mg (30% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.70 (s, 1H), 8.39 (s, 1H), 8.02 (d,1H), 7.58-7.69 (m, 1H), 7.36 (d, 1H), 6.95-7.11 (m, 2H), 6.24-6.44 (m,3H), 5.49 (s, 1H), 4.06 (s, 2H), 3.35-3.44 (m, 2H), 2.81 (t, 2H), 1.27(s, 6H).

Example 52-{3-[2-(dimethylamino)ethoxy]pyridin-4-yl}-3-[(3-fluorophenyl)amino]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 1; Intermediate 6-5(181 mg, 408 μmol) as the starting material, the title compound wasprepared 5.0 mg (3% yield).

1H-NMR (400 MHz, DMSO-d6): Shift [ppm]=11.82 (s, 1H), 10.91 (br s, 1H),8.56 (s, 1H), 8.32 (d, 1H), 8.11 (br s, 1H), 7.70 (d, 1H), 7.31 (br s,1H), 7.01-7.09 (m, 1H), 6.34-6.47 (m, 3H), 4.55-4.63 (m, 2H), 3.43 (brt,3H), 2.98 (t, 2H), 2.78-2.89 (m, 6H).

Example 63-[(3-fluorophenyl)amino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

N-(3-fluorophenyl)-4-({[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide(Intermediate 6-6; 217 mg, 90% purity, 426 μmol) in MeOH (8 ml) wasadded TFA (33 μl, 430 μmol) followed by aqueous hydrogen peroxide (87μl, 30% purity, 850 μmol) and heated at 50° C. for 16 h. The reactionmixture was allowed to ccol sat. sodium thiosulfate solution and TEA(0.5 ml) were added and the reaction mixture was extracted with DCM, theorganics were dried with Na2SO4, filtered and concentrated in vacuo. Theresidue was purified twice by preparative TLC (DCM:EtOH) to give thetitled compound 31.7 mg (17% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.19 (s, 1H), 8.41 (s, 1H), 8.03 (d,1H), 7.62 (s, 1H), 7.38 (d, 1H), 6.99-7.10 (m, 2H), 6.42 (d, 1H), 6.35(t, 1H), 6.26 (dt, 1H), 4.17 (s, 2H), 3.38-3.44 (m, 2H), 3.25 (s, 3H),2.83 (t, 2H), 1.27 (s, 6H).

Example 73-[(3-fluorophenyl)amino]-2-{3-[2-methyl-2-(morpholin-4-yl)propoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 6; Intermediate 6-7(220 mg, 428 μmol) as the starting material, the title compound wasprepared 44.0 mg (19% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.16 (s, 1H), 8.41 (s, 1H), 8.00 (d,1H), 7.41 (s, 1H), 7.29 (d, 1H), 7.15 (s, 1H), 6.67 (m, 1H), 6.51 (m,1H), 6.03 (d, 1H), 4.16-4.23 (m, 4H), 3.73 (m, 2H), 3.38-3.49 (m, 2H),3.32 (s, 3H), 3.25 (s, 3H), 2.83 (t, 2H), 1.28 (s, 6H).

Example 83-[(3-fluorophenyl)amino]-2-(3-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 6; Intermediate 6-8(300 mg, 543 μmol) as the starting material, the title compound wasprepared 8.0 mg (3% yield) after preparative HPLC (acidic method).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.06 (s, 1H), 8.43 (s, 1H), 7.99 (d,1H), 7.70 (s, 1H), 7.41 (d, 1H), 7.09 (s, 1H), 7.00-7.07 (m, 1H), 6.42(m, 1H), 6.36 (m, 1H), 6.28 (dt, 1H), 4.49 (m, 1H), 4.19 (m, 1H),3.36-3.45 (m, 2H), 3.15-3.22 (m, 1H), 2.75-2.89 (m, 2H), 2.30-2.33 (m,3H), 1.69-2.01 (m, 4H).

Example 93-[(3,5-difluorophenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 1; Intermediate 6-9(124 mg, 276 μmol) as the starting material, the title compound wasprepared 32 mg (27% yield).

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm]=11.18 (s, 1H), 8.42 (s, 1H), 8.10 (d,1H), 7.82 (s, 1H), 7.36 (d, 1H), 7.05 (s, 1H), 6.25 (tt, 1H), 6.14 (brd,1H), 6.10-6.13 (m, 1H), 4.31 (m, 2H), 3.71-3.76 (m, 2H), 3.41 (m, 2H),3.37 (s, 3H), 2.84 (t, 2H).

Example 103-[(3,5-difluorophenyl)amino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 6; Intermediate 6-10(210 mg, 375 μmol) as the starting material, the title compound wasprepared 69 mg (40% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.25 (s, 1H), 8.43 (s, 1H), 8.09 (d,1H), 7.88 (s, 1H), 7.38 (d, 1H), 7.07 (s, 1H), 6.26 (tt, 1H), 6.15 (brd, 1H), 6.10-6.13 (m, 1H), 4.15 (s, 2H), 3.36-3.44 (m, 2H), 3.24 (s,3H), 2.83 (t, 2H), 1.25 (s, 6H).

Example 113-{[2-(difluoromethoxy)phenyl]amino}-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 1; Intermediate 6-11((1.03 g, 2.15 mmol) as the starting material, the title compound wasprepared 562 mg (59% yield) after silica chromatography (DCM:MeOH) andfurther purification of impure fraction by preparative HPLC (acidicmethod).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.06 (s, 1H), 8.40 (s, 1H), 8.00 (d,1H), 7.01-7.42 (m, 5H), 6.79 (t, 1H), 6.66 (m, 1H), 6.31 (m, 1H), 4.31(m, 2H), 3.74-3.80 (m, 2H), 3.35-3.44 (m, 5H), 2.85 (t, 2H).

Example 123-[(2-bromo-3-fluorophenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 1; Intermediate 6-12(28.0 mg, 55.0 μmol) as the starting material and heated for 5 h, thetitle compound was prepared 3.0 mg (10% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.19 (s, 1H), 8.39 (s, 1H),8.02-8.09 (m, 1H), 7.58 (s, 1H), 7.22 (d, 1H), 7.17 (s, 1H), 6.91 (m,1H), 6.60 (m, 1H), 6.13 (d, 1H), 4.23-4.30 (m, 2H), 3.71-3.77 (m, 2H),3.40-3.47 (m, 2H), 3.35 (s, 3H), 2.86 (t, 2H).

Example 132-[3-(2-methoxyethoxy)pyridin-4-yl]-3-[(2-methoxyphenyl)amino]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 1; Intermediate 6-13(85.0 mg, 192 μmol) as the starting material and heated for 2 h, thetitle compound was prepared 15.0 mg (17% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.96 (s, 1H), 8.33-8.41 (m, 1H),7.96 (d, 1H), 7.52 (s, 1H), 7.10-7.18 (m, 2H), 6.90 (m, 1H), 6.62 (m,1H), 6.48 (m, 1H), 6.15 (m, 1H), 4.25-4.31 (m, 2H), 3.87 (s, 3H),3.75-3.82 (m, 2H), 3.36-3.46 (m, 5H), 2.84 (t, 2H).

Example 142-[3-(2-methoxyethoxy)pyridin-4-yl]-3-{[2-(trifluoromethoxy)phenyl]amino}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 1; Intermediate 6-14(152.0 mg, 306 μmol) as the starting material and heated for 2 h, thetitle compound was prepared 52.0 mg (35% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.08 (s, 1H), 8.40 (s, 1H), 7.99 (d,1H), 7.56 (s, 1H), 7.24 (s, 1H), 7.21-7.24 (m, 1H), 7.14 (s, 1H), 6.91(t, 1H), 6.69 (m, 1H), 6.37 (m, 1H), 4.31 (m, 2H), 3.76 (m, 2H), 3.43(m, 2H), 3.38 (s, 3H), 2.86 (t, 2H).

Example 153-{[2-(2,2-difluoroethyl)phenyl]amino}-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 1; Intermediate 6-15(126 mg, 264 μmol) as the starting material and heated for 2 h, thetitle compound was prepared 20.0 mg (16% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.99 (s, 1H), 8.40 (s, 1H), 7.96 (d,1H), 7.31 (d, 2H), 7.07-7.23 (m, 2H), 6.86 (t, 1H), 6.66 (m, 1H),6.30-6.63 (m, 2H), 4.36 (m, 2H), 3.79 (m, 2H), 3.41 (s, 3H) 3.21-3.46(m, 4H), 2.87 (t, 2H).

Example 163-[(3-fluoro-2-methoxyphenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 1; Intermediate 6-16(115 mg, 250 μmol) as the starting material and heated for 2 h, thetitle compound was prepared 46.0 mg (41% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.03 (s, 1H), 8.41 (s, 1H), 8.03 (d,1H), 7.52 (s, 1H), 7.29 (d, 1H), 7.15 (s, 1H), 6.64 (m, 1H), 6.49 (m,1H), 6.01 (d, 1H), 4.34 (m, 2H), 3.89-3.93 (m, 3H), 3.78 (m, 2H), 3.39(s, 4H), 2.85 (t, 2H).

Example 173-[(3-fluoro-2-methoxyphenyl)amino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 6; Intermediate 6-17(3.50 g, 7.16 mmol) as the starting material, the title compound wasprepared after crystallization from EtOH (1.24 g, 36% yield). Furthercrystallization of the mother liquor gave (300 mg, 9% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.17 (s, 1H), 8.42 (s, 1H), 8.01 (d,1H), 7.51 (s, 1H), 7.28 (d, 1H), 7.17 (s, 1H), 6.66 (m, 1H), 6.51 (m,1H), 6.03 (d, 1H), 4.19 (s, 2H), 3.91 (s, 3H), 3.42 (m, 2H), 3.25 (s,3H), 2.78-2.86 (m, 2H), 1.28 (s, 6H).

Example 183-{[2-(difluoromethoxy)-3-fluorophenyl]amino}-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 1; Intermediate 6-18(99.0 mg, 199 μmol) as the starting material and heated for 2 h, thetitle compound was prepared 20.0 mg (21% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.11 (s, 1H), 8.42 (s, 1H), 8.04 (d,1H), 7.42 (s, 1H), 7.33-7.37 (m, 1H), 7.09-7.15 (m, 1H), 6.98-7.38 (m,1H), 6.84 (m, 1H), 6.57 (m, 1H), 6.13 (d, 1H), 4.26-4.39 (m, 2H),3.74-3.80 (m, 2H), 3.41 (m, 2H), 3.37 (s, 3H), 2.85 (t, 2H).

Example 193-{[2-(difluoromethoxy)-3-fluorophenyl]amino}-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 6; Intermediate 6-19(160 mg, 305 μmol) as the starting material, the title compound wasprepared (61 mg, 39% yield) after preparative TLC purification(DCM:MeOH).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.22 (s, 1H), 8.42 (s, 1H), 8.02 (d,1H), 7.45 (s, 1H), 7.34-7.38 (m, 1H), 7.14 (m, 1H), 7.00-7.40 (m, 1H),6.87 (m, 1H), 6.59 (m, 1H), 6.14 (d, 1H), 4.17 (s, 2H), 3.39-3.45 (m,2H), 3.24 (s, 3H), 2.84 (t, 2H), 1.27 (s, 6H).

Example 203-[(3-fluoro-2-methylphenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 1; Intermediate 6-20(140 mg, 315 μmol) as the starting material and heated for 2 h, thetitle compound was prepared 33.0 mg (23% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.00 (s, 1H), 8.39 (s, 1H), 7.99 (d,1H), 7.32 (s, 1H), 7.24 (d, 1H), 7.18 (s, 1H), 6.72-6.84 (m, 1H), 6.46(t, 1H), 6.07 (d, 1H), 4.29-4.36 (m, 2H), 3.74-3.80 (m, 2H), 3.37-3.46(m, 5H), 2.86 (t, 2H), 2.18 (d, 3H).

Example 213-[(3-fluoro-2-methylphenyl)amino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 6; Intermediate 6-21(220 mg, 466 μmol) as the starting material, the title compound wasprepared (5 mg, 2% yield) after preparative two separate TLCpurifications (DCM:MeOH).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.15 (s, 1H), 8.39 (s, 1H), 7.97 (d,1H), 7.31 (s, 1H), 7.23 (d, 1H), 7.19 (s, 1H), 6.76-6.82 (m, 1H), 6.48(t, 1H), 6.09 (d, 1H), 4.18 (s, 2H), 3.39-3.46 (m, 2H), 3.26 (s, 3H),2.84 (t, 2H), 2.18-2.21 (m, 3H), 1.28 (s, 6H).

Example 223-{[2-(2,2-difluoroethyl)-3-fluorophenyl]amino}-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 1; Intermediate 6-22(140 mg, 283 μmol) as the starting material and heated for 5 h. After 5h another portion of aqueous hydrogen peroxide was added and heated at90° C. for a further 2 h. The title compound was prepared 20.0 mg (15%yield) after preparative HPLC (basic method) and silica chromatography(DCM:MeOH).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.05 (s, 1H), 8.40 (br s, 1H), 8.00(br s, 1H), 7.36-7.39 (m, 1H), 7.33 (s, 1H), 7.09 (s, 1H), 6.85-6.92 (m,1H), 6.42-6.50 (m, 1H), 6.43 (br t, 1H), 6.13 (d, 1H), 4.34 (m, 2H),3.77 (m, 2H), 3.23-3.45 (m, 7H), 2.82-2.94 (m, 2H).

Example 233-{[2-(2,2-difluoroethyl)-3-fluorophenyl]amino}-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 6; Intermediate 6-23(220 mg, 466 μmol) as the starting material, the title compound wasprepared (31 mg, 17% yield) after preparative separate TLC purification(DCM:MeOH).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.18 (s, 1H), 8.40 (s, 1H), 7.98 (d,1H), 7.35-7.40 (m, 2H), 7.11 (s, 1H), 6.87-6.93 (m, 1H), 6.29-6.65 (m,2H), 6.13 (d, 1H), 4.17 (s, 2H), 3.23-3.44 (m, 7H), 2.84 (t, 2H), 1.27(s, 6H).

Example 243-[(3-fluoro-2-hydroxyphenyl)amino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

To a solution of Intermediate 7-24 (30.0 mg, 62.4 μmol) in MeOH (0.5 ml)under an argon atmosphere was added Pd/C 5% on activated charcoal (2mg), followed by ammonium formate (23.6 mg, 375 μmol). The reaction washeated under reflux conditions for 16 h. Another portion of ammoniumformate (23.6 mg, 375 μmol) was added and heated at reflux for 24 h. Afurther portion of ammonium formate (3 eq) was added and heated atreflux for 24 h. A further portion of ammonium formate (2 eq) was addedand heated at reflux for 24 h. The reaction mixture was allowed to cooltor RT, filtered and the catalyst was washed with MeOH. The filtrate wasconcentrated and the residue purified by preparative TLC (DCM:MeOH) togive the title compound (2 mg, 7% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.05-11.17 (m, 1H), 8.38 (s, 1H),7.95 (d, 1H), 7.53 (s, 1H), 7.19 (brs, 1H), 7.15 (d, 1H), 6.42-6.50 (m,1H), 6.28-6.40 (m, 1H), 5.96 (br d, 1H), 3.42 (m, 2H), 3.26 (s, 3H),2.81-2.85 (m, 2H), 1.29 (s, 6H).

Example 253-[(2-ethoxy-3-fluorophenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 1; Intermediate 6-25(130 mg, 274 μmol) as the starting material and heated for 5 h, thetitle compound was prepared 31.0 mg (23% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.00 (s, 1H), 8.40 (s, 1H), 8.01 (d,1H), 7.56-7.63 (m, 1H), 7.23 (d, 1H), 7.17 (brs, 1H), 6.61 (m, 1H), 6.49(m, 1H), 5.99 (d, 1H), 4.29-4.37 (m, 2H), 4.14 (q, 2H), 3.78 (m, 2H),3.36-3.44 (m, 5H), 2.85 (t, 2H), 1.41 (t, 3H).

Example 263-[(2-ethoxy-3-fluorophenyl)amino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 6; Intermediate 6-26(200 mg, 398 μmol) as the starting material, the title compound wasprepared (43 mg, 22% yield) after two separate preparative TLCpurifications (DCM:MeOH).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.15 (s, 1H), 8.41 (s, 1H), 7.99 (d,1H), 7.58 (s, 1H), 7.22 (d, 1H), 7.18-7.20 (m, 1H), 6.65 (m, 1H), 6.51(t, 1H), 6.02 (d, 1H), 4.08-4.22 (m, 4H), 3.43 (m, 2H), 3.25 (s, 3H),2.83 (t, 2H), 1.41 (t, 3H).

Example 27

3-{[2-(2,2-difluoroethoxy)-3-fluorophenyl]amino}-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 6; Intermediate 6-27(220 mg, 408 μmol) as the starting material, the title compound wasprepared (80 mg, 37% yield) after preparative TLC purification(DCM:MeOH).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.19 (s, 1H), 8.42 (s, 1H), 8.02 (d,1H), 7.38 (s, 1H), 7.36 (d, 1H), 7.15-7.21 (m, 1H), 6.73 (m, 1H),6.49-6.57 (m, 1H), 6.50 (br t, 1H), 6.05 (d, 1H), 4.38 (m, 2H), 4.19 (s,2H), 3.35-3.45 (m, 2H), 3.25 (s, 3H), 2.84 (t, 2H), 1.28 (s, 6H).

Example 28

3-[(3,4-difluoro-2-methoxyphenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 1; Intermediate 6-28(115 mg, 240 μmol) as the starting material and heated for 2 h, thetitle compound was prepared 51.0 mg (45% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.04 (s, 1H), 8.42 (s, 1H), 8.04 (d,1H), 7.39 (s, 1H), 7.28 (d, 1H), 7.15 (s, 1H), 6.69-6.78 (m, 1H), 5.94(m, 1H), 4.34 (m, 2H), 3.97 (s, 3H), 3.78 (m, 2H), 3.38-3.45 (m, 5H),2.85 (t, 2H).

Example 293-[(3,4-difluoro-2-methoxyphenyl)amino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 8; Intermediate 6-29(240 mg, 474 μmol) as the starting material, the title compound wasprepared (80 mg, 34% yield) after preparative TLC purification(DCM:MeOH).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.17 (s, 1H), 8.42 (s, 1H), 8.03 (d,1H), 7.39 (s, 1H), 7.27 (d, 1H), 7.17 (s, 1H), 6.72-6.80 (m, 1H), 5.95(m, 1H), 4.19 (s, 2H), 3.96-4.01 (m, 3H), 3.42 (m, 2H), 3.25 (s, 3H),2.83 (t, 2H), 1.28 (s, 6H).

Example 303-[(3,5-difluoro-2-methoxyphenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 1; Intermediate 6-30(160 mg, 334 μmol) as the starting material and heated for 2 h, thetitle compound was prepared 57.0 mg (36% yield).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.17 (s, 1H), 8.44 (s, 1H), 8.10 (d,1H), 7.62 (s, 1H), 7.32 (d, 1H), 7.12 (s, 1H), 6.43 (m, 1H), 5.73 (dt,1H), 4.27-4.35 (m, 2H), 3.85 (s, 3H), 3.71-3.77 (m, 2H), 3.42 (m, 2H),3.35 (s, 3H), 2.89-2.96 (m, 1H), 2.85 (t, 1H).

Example 313-[(3,5-difluoro-2-methoxyphenyl)amino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 6; Intermediate 6-31(250 mg, 494 μmol) as the starting material, the title compound wasprepared (103 mg, 42% yield) after concentration of the reaction mixtureand crystallization from DMSO.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.25 (s, 1H), 8.45 (s, 1H), 8.08 (d,1H), 7.60 (s, 1H), 7.33 (d, 1H), 7.13 (s, 1H), 6.44 (m, 1H), 5.71-5.76(m, 1H), 4.15 (s, 2H), 3.85 (s, 3H), 3.38-3.46 (m, 2H), 3.22 (s, 3H),2.84 (t, 2H), 1.25 (s, 6H).

Example 323-(3-chloro-2-methoxyanilino)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

N-(3-chloro-2-methoxyphenyl)-4-({[3-(2-methoxyethoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide(intermediate 6-32, 119 mg, 249 μmol) was solubilised in 5.0 mLmethanol, trifluoroacetic acid (19 μL, 250 μmol) and hydrogen peroxide(44 μL, 35% purity, 500 μmol) were added and the mixture was stirredover night at 50° C. The reaction mixture was quenched with a saturatedaqueous sodium thiosulfate solution and stirred for 2 h. The mixture wasdiluted with triethylamine (72.9 μL, 726 μmol) and water and extractedwith dichloromethane two times. The combined organic layers werefiltered through a waterresistant filter, the filtrate was concentratedunder reduced pressure and the residue was purified by preparative HPLCto give 30.7 mg of the title compound (99% purity, 28% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.332 (0.65), 2.518 (3.28), 2.523(2.30), 2.673 (0.65), 2.839 (0.86), 2.857 (1.88), 2.874 (0.96), 3.389(16.00), 3.401 (0.76), 3.407 (0.74), 3.418 (1.26), 3.423 (1.23), 3.435(0.62), 3.441 (0.57), 3.768 (1.23), 3.779 (1.50), 3.791 (1.34), 3.878(11.67), 4.336 (1.28), 4.347 (1.48), 4.359 (1.20), 6.138 (1.05), 6.152(1.17), 6.162 (1.09), 6.675 (4.15), 6.685 (2.40), 6.688 (2.22), 7.150(1.14), 7.278 (1.91), 7.290 (1.93), 7.526 (2.37), 8.028 (2.56), 8.041(2.36), 8.419 (3.42), 11.052 (1.20).

LC-MS (method 2): R, =1.00 min; MS (ESIpos): m/z=443 [M+H]⁺

The examples in Table 3 were prepared analogous to the preparation ofexample 32 starting from the corresponding intermediates 6-x.

TABLE 3 Structure Example Name Analytical Data 33

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.006 (1.16), 0.007 (1.06), 1.283(16.00), 2.368 (0.57), 2.518 (2.55), 2.522 (2.45), 2.525 (2.02), 2.543(0.67), 2.830 (0.73), 2.844 (1.59), 2.857 (0.82), 3.257 (12.80), 3.415(0.50), 3.420 (0.53), 3.428 (1.02), 3.433 (0.97), 3.442 (0.49), 3.447(0.44), 3.894 (10.71), 4.193 (4.06), 5.752 (2.91), 6.163 (0.90), 6.170(0.73), 6.175 (0.90), 6.182 (0.92), 6.697 (3.93), 6.704 (1.79), 6.709(1.62), 7.165 (0.89), 7.270 (1.56), 7.280 (1.56), 7.521 (2.05), 8.009(1.89), 8.019 (1.73), 8.314 (0.97), 8.417 (2.58), 11.180 (0.95). LC-MS(method 1): Rt = 0.89 min; m/z = 471 (M + H)+3-(3-chloro-2-methoxyanilino)-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2- c]pyridin-4-one 34

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.052 (0.52), 1.221 (0.50), 1.258(16.00), 2.518 (1.08), 2.522 (0.69), 2.829 (0.81), 2.846 (1.72), 2.863(0.90), 3.230 (13.03), 3.408 (0.60), 3.414 (0.65), 3.425 (1.16), 3.431(1.15), 3.442 (0.59), 3.448 (0.53), 4.158 (4.34), 6.289 (1.04), 6.293(1.06), 6.309 (1.11), 6.313 (1.02), 6.861 (0.68), 6.866 (0.81), 6.881(1.80), 6.886 (1.55), 6.903 (1.37), 6.922 (1.63), 6.942 (0.57), 7.174(1.06), 7.235 (1.76), 7.248 (1.78), 7.619 (2.36), 8.030 (2.37), 8.043(2.17), 8.424 (3.12), 11.266 (1.11). LC-MS (method 2): Rt = 1.15 min;m/z = 475 (M + H)⁺ 3-(2,3-dichloroanilino)-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2- c]pyridin-4-one 35

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.172 (0.60), 1.214 (1.49), 1.233(3.96), 1.252 (1.65), 1.282 (16.00), 1.987 (0.98), 2.518 (0.99), 2.522(0.62), 2.539 (0.62), 2.703 (0.78), 2.720 (0.78), 2.829 (0.75), 2.846(1.64), 2.864 (0.85), 3.250 (0.43), 3.259 (12.16), 3.417 (0.54), 3.423(0.59), 3.434 (1.14), 3.440 (1.05), 3.451 (0.53), 3.457 (0.48), 4.186(4.11), 6.110 (0.98), 6.131 (1.02), 6.449 (0.46), 6.471 (0.82), 6.492(0.53), 6.768 (0.75), 6.785 (0.73), 7.183 (2.04), 7.195 (1.89), 7.396(1.82), 7.936 (1.42), 7.949 (1.35), 8.388 (2.17), 11.142 (1.04). LC-MS(method 2): Rt = 1.17 min; m/z = 453 (M + H)+3-(2-ethyl-3-fluoroanilino)-2-[3-(2- methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2- c]pyridin-4-one 36

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.171 (0.67), 1.232 (0.85), 1.241(0.68), 1.278 (16.00), 2.361 (7.22), 2.518 (2.02), 2.522 (1.27), 2.669(0.50), 2.829 (0.75), 2.846 (1.62), 2.863 (0.84), 3.173 (0.43), 3.178(0.68), 3.255 (12.52), 3.410 (0.56), 3.416 (0.60), 3.428 (1.10), 3.433(1.07), 3.444 (0.53), 3.450 (0.49), 4.184 (4.08), 6.215 (0.83), 6.218(0.83), 6.235 (0.90), 6.238 (0.84), 6.735 (0.56), 6.738 (0.65), 6.754(1.42), 6.758 (1.19), 6.778 (1.00), 6.797 (1.18), 6.818 (0.41), 7.193(1.00), 7.221 (1.67), 7.233 (1.69), 7.331 (1.90), 7.972 (2.20), 7.985(2.06), 8.399 (2.98), 11.163 (1.04). LC-MS (method 1): Rt = 0.93 min;m/z = 455 (M + H)+ 3-(3-chloro-2-methylanilino)-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2- c]pyridin-4-one 37

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.263 (16.00), 2.518 (2.79), 2.523(1.84), 2.830 (0.79), 2.847 (1.73), 2.864 (0.89), 3.234 (12.43), 3.413(0.58), 3.419 (0.62), 3.430 (1.12), 3.436 (1.11), 3.447 (0.55), 3.453(0.51), 4.166 (4.32), 6.153 (0.99), 6.174 (1.02), 6.606 (0.50), 6.609(0.51), 6.627 (0.97), 6.630 (0.95), 6.647 (0.57), 6.651 (0.53), 6.928(0.43), 6.944 (0.51), 6.949 (0.81), 6.965 (0.80), 6.969 (0.45), 7.179(1.66), 7.192 (2.58), 7.543 (2.29), 8.007 (1.42), 8.019 (1.34), 8.135(0.67), 8.418 (2.24), 11.250 (1.11). LC-MS (method 1): Rt = 0.79 min;m/z = 503 (M + H)+ 3-(2-bromo-3-fluoroanilino)-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2- c]pyridin-4-one 38

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (0.71), 1.173 (1.53), 1.190(0.80), 1.230 (0.60), 1.235 (1.15), 1.267 (16.00), 1.988 (2.92), 2.518(1.22), 2.523 (0.82), 2.820 (0.78), 2.838 (1.68), 2.855 (0.87), 3.218(0.86), 3.239 (13.11), 3.400 (0.57), 3.406 (0.63), 3.416 (1.12), 3.423(1.11), 3.434 (0.55), 3.440 (0.50), 4.017 (0.65), 4.035 (0.64), 4.178(4.17), 6.275 (1.01), 6.278 (1.06), 6.295 (1.06), 6.299 (1.03), 6.785(0.93), 6.789 (1.04), 6.805 (1.50), 6.809 (1.35), 6.865 (1.18), 6.886(1.70), 6.906 (0.68), 7.027 (0.80), 7.155 (1.04), 7.212 (1.65), 7.333(1.75), 7.345 (1.78), 7.398 (0.73), 7.434 (2.18), 8.012 (2.46), 8.025(2.24), 8.425 (3.13), 11.226 (1.11). 3-[3-chloro-2- LC-MS (method 2): Rt= 1.14 min; (difluoromethoxy)anilino]-2-[3-(2- m/z = 507 (M + H)+methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2- c]pyridin-4-one 39

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.273 (16.00), 1.988 (0.75), 2.518(0.60), 2.523 (0.46), 2.831 (0.74), 2.848 (1.63), 2.865 (0.83), 3.330(13.28), 3.416 (0.53), 3.422 (0.58), 3.433 (1.05), 3.439 (1.02), 3.450(0.50), 3.456 (0.45), 4.174 (4.17), 6.345 (0.90), 6.348 (0.92), 6.365(0.97), 6.369 (0.92), 6.656 (0.52), 6.660 (0.53), 6.675 (0.84), 6.679(0.80), 6.694 (0.64), 6.698 (0.58), 6.880 (0.51), 6.884 (0.51), 6.901(0.77), 7.157 (1.75), 7.169 (1.77), 7.203 (0.95), 7.334 (1.10), 7.338(1.16), 7.354 (1.08), 7.357 (1.03), 7.553 (2.12), 7.976 (2.39), 7.988(2.21), 8.409 (3.09), 11.208 (0.97). LC-MS (method 1): Rt = 0.82 min;3-(2-chloroanilino)-2-[3-(2-methoxy-2- MS (ESIneg): m/z = 439 [M − H]⁻methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4- one 40

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.215 (0.56), 1.218 (0.73), 1.254(16.00), 2.128 (3.69), 2.518 (1.88), 2.522 (1.18), 2.831 (0.72), 2.848(1.59), 2.865 (0.82), 3.173 (0.58), 3.205 (0.42), 3.230 (12.58), 3.408(0.59), 3.414 (0.61), 3.425 (1.08), 3.431 (1.06), 3.442 (0.53), 3.448(0.48), 4.158 (4.03), 5.772 (0.51), 5.802 (0.49), 6.383 (0.51), 6.388(0.53), 7.163 (0.91), 7.306 (1.23), 7.318 (1.26), 7.428 (1.23), 8.056(1.02), 8.069 (0.96), 8.441 (1.61), 11.235 (0.96). LC-MS (method 1): Rt= 0.93 min; m/z = 457 (M + H)+ 3-(3,5-difluoro-2-methylanilino)-2-[3-(2-methoxy-2-methylpropoxy)pyridin- 4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 41

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.251 (16.00), 2.518 (0.91), 2.523(0.59), 2.826 (0.77), 2.843 (1.68), 2.860 (0.87), 3.224 (12.69), 3.415(0.65), 3.420 (0.70), 3.432 (1.17), 3.437 (1.16), 3.449 (0.59), 3.454(0.54), 4.151 (4.17), 6.354 (0.84), 6.375 (0.86), 6.599 (0.43), 6.620(0.49), 6.629 (0.46), 6.649 (0.45), 7.159 (0.63), 7.174 (1.55), 7.220(1.25), 7.233 (1.26), 7.718 (0.89), 7.723 (0.91), 8.006 (0.93), 8.019(0.89), 8.416 (1.49), 11.257 (1.06).3-[3-fluoro-2-(trifluoromethyl)anilino]- 2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4- one 42

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.273 (16.00), 2.518 (0.74), 2.522(0.46), 2.836 (0.77), 2.853 (1.68), 2.870 (0.86), 3.247 (13.32), 3.431(0.56), 3.437 (0.60), 3.448 (1.09), 3.454 (1.08), 3.465 (0.53), 3.471(0.49), 4.179 (4.21), 6.582 (0.89), 6.602 (0.94), 6.808 (0.41), 6.827(0.83), 6.845 (0.47), 7.108 (1.63), 7.121 (1.66), 7.162 (0.42), 7.181(0.71), 7.201 (0.45), 7.219 (0.99), 7.533 (0.80), 7.551 (0.74), 7.678(1.41), 7.898 (1.76), 7.911 (1.65), 8.397 (2.53), 11.191 (1.03). LC-MS(method 2): Rt = 1.13 min; m/z = 475 (M + H)+ 2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-3-[2- (trifluoromethyl)anilino]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4- one 43

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.172 (0.46), 1.239 (16.00), 2.084(0.47), 2.518 (0.91), 2.523 (0.69), 2.820 (0.70), 2.837 (1.54), 2.854(0.79), 3.212 (14.17), 3.397 (0.51), 3.403 (0.55), 3.414 (1.00), 3.420(0.98), 3.430 (0.48), 3.437 (0.46), 4.140 (3.95), 5.758 (2.83), 5.814(0.41), 5.817 (0.49), 5.822 (0.46), 5.843 (0.42), 5.845 (0.48), 5.850(0.40), 6.542 (0.40), 6.547 (0.45), 6.550 (0.48), 6.554 (0.45), 6.962(0.55), 7.113 (0.93), 7.147 (1.09), 7.332 (0.50), 7.405 (1.60), 7.418(1.62), 7.670 (1.23), 7.674 (1.28), 8.079 (2.44), 8.091 (2.09), 8.448(2.95), 11.299 (0.98). LC-MS (method 2): Rt = 1.13 min; m/z = 509 (M +H)+ 3-[2-(difluoromethoxy)-3,5- difluoroanilino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4- one 44

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.227 (0.63), 1.248 (0.52), 1.277(16.00), 2.518 (1.85), 2.523 (1.24), 2.823 (0.76), 2.840 (1.67), 2.857(0.87), 3.167 (0.42), 3.251 (12.86), 3.405 (0.55), 3.411 (0.60), 3.422(1.11), 3.428 (1.11), 3.439 (0.53), 3.445 (0.51), 3.926 (10.48), 4.192(4.19), 6.127 (0.81), 6.141 (0.85), 6.151 (0.94), 6.164 (0.89), 6.792(0.88), 6.815 (1.66), 6.838 (0.81), 7.172 (1.05), 7.264 (1.71), 7.277(1.74), 7.407 (2.29), 8.022 (2.12), 8.034 (1.99), 8.421 (2.99), 11.184(1.10). LC-MS (method 2): Rt = 1.14 min; MS (ESIpos): m/z = 489 [M + H]⁺3-(3-chloro-4-fluoro-2- methoxyanilino)-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4- one 45

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.218 (0.59), 1.233 (0.72), 1.270(16.00), 2.250 (5.44), 2.327 (0.47), 2.522 (1.71), 2.539 (0.66), 2.669(0.48), 2.831 (0.79), 2.849 (1.70), 2.866 (0.88), 3.245 (12.24), 3.422(0.67), 3.433 (1.14), 3.439 (1.14), 3.450 (0.58), 3.456 (0.53), 4.177(4.14), 5.759 (1.57), 5.903 (0.69), 5.909 (0.76), 5.933 (0.69), 5.939(0.73), 6.351 (0.41), 6.364 (0.73), 6.371 (0.75), 6.392 (0.41), 7.048(0.53), 7.067 (0.80), 7.085 (0.53), 7.203 (1.46), 7.216 (0.87), 7.334(1.48), 7.996 (0.41), 8.426 (0.53), 11.179 (1.05). LC-MS (method 2): Rt= 1.08 min; 3-(5-fluoro-2-methylanilino)-2-[3-(2- m/z = 439 (M + H)+methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2- c]pyridin-4-one 46

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.035 (1.06), 1.052 (2.48), 1.070(1.22), 2.518 (0.47), 2.843 (0.46), 2.860 (1.00), 2.877 (0.52), 3.332(16.00), 3.354 (9.29), 3.405 (0.41), 3.422 (0.93), 3.429 (0.67), 3.434(0.50), 3.439 (0.61), 3.720 (0.67), 3.729 (0.69), 3.732 (0.80), 3.735(0.66), 3.743 (0.74), 4.259 (0.69), 4.267 (0.63), 4.271 (0.78), 4.282(0.65), 6.268 (0.65), 6.272 (0.66), 6.287 (0.70), 6.292 (0.66), 6.841(0.54), 6.856 (1.35), 6.860 (1.02), 6.869 (0.98), 6.888 (1.00),3-(2,3-dichloroanilino)-2-[3-(2- 7.157 (0.60), 7.250 (1.07), 7.263methoxyethoxy)pyridin-4-yl]-1,5,6,7- (1.09), 7.634 (1.37), 8.065 (1.61),tetrahydro-4H-pyrrolo[3,2-c]pyridin-4- 8.078 (1.47), 8.399 (1.90),11.203 one (0.62). LC-MS (method 2): Rt = 1.05 min; m/z = 447 (M + H)+47

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (1.07), 2.522 (0.67), 2.852(0.77), 2.869 (1.71), 2.886 (0.88), 3.373 (16.00), 3.425 (0.69), 3.431(0.71), 3.442 (1.19), 3.448 (1.16), 3.459 (0.60), 3.465 (0.56), 3.746(1.10), 3.758 (1.30), 3.762 (1.14), 3.770 (1.23), 4.310 (1.14), 4.319(1.07), 4.323 (1.29), 4.334 (1.06), 6.556 (0.90), 6.577 (0.95), 6.785(0.41), 6.804 (0.84), 6.823 (0.49), 7.130 (0.42), 7.150 (2.27), 7.163(1.78), 7.203 (1.11), 7.516 (0.80), 7.532 (0.75), 7.535 (0.74), 7.705(1.36), 7.950 (1.73), 7.963 (1.60), 8.133 (1.08), 8.394 (2.61), 11.090(1.02). LC-MS (method 1): Rt = 0.84 min; m/z = 446 (M + H)+2-[3-(2-methoxyethoxy)pyridin-4-yl]-3-[2-(trifluoromethyl)anilino]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4- one 48

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.815 (0.40), 0.821 (0.40), 0.904(0.44), 1.154 (4.31), 1.172 (8.82), 1.190 (4.36), 1.735 (0.53), 1.755(0.53), 1.987 (16.00), 2.074 (4.29), 2.309 (1.34), 2.317 (6.58), 2.326(0.75), 2.332 (0.73), 2.518 (1.79), 2.522 (1.16), 2.575 (0.45), 2.669(0.41), 2.798 (0.56), 2.853 (0.47), 3.192 (0.41), 3.415 (0.47), 3.432(0.84), 3.448 (0.41), 3.901 (8.47), 4.000 (1.20), 4.017 (3.60), 4.035(3.61), 4.053 (1.21), 4.183 (0.43), 4.191 (0.45), 4.209 (0.52), 4.217(0.49), 4.510 (0.56), 4.514 (0.61), 4.535 (0.50), 4.540 (0.47), 6.148(0.75), 6.158 (0.68), 6.162 3-(3-chloro-2-methoxyanilino)-2-(3- (0.76),6.172 (0.75), 6.707 (3.18), {[(2S)-1-methylpyrrolidin-2- 6.717 (1.60),6.721 (1.46), 7.160 yl]methoxy}pyridin-4-yl)-1,5,6,7- (0.87), 7.283(1.46), 7.296 (1.44), tetrahydro-4H-pyrrolo[3,2-c]pyridin-4- 7.586(1.84), 7.974 (1.84), 7.986 one (1.71), 8.438 (2.59), 12.130 (0.84).LC-MS (method 2): Rt = 1.13 min; MS (ESIpos): m/z = 482 [M + H]⁺ 49

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.833 (0.52), 0.852 (0.92), 1.232(4.76), 1.256 (0.85), 1.717 (0.57), 1.724 (0.65), 1.741 (1.20), 1.760(1.28), 1.781 (0.59), 1.848 (0.54), 1.868 (0.60), 1.884 (0.49), 1.907(0.77), 1.947 (0.81), 1.957 (0.42), 1.967 (0.83), 1.978 (0.55), 1.987(0.45), 1.997 (0.43), 2.205 (8.12), 2.208 (8.14), 2.293 (0.57), 2.318(16.00), 2.337 (1.46), 2.361 (0.55), 2.518 (2.55), 2.523 (1.71), 2.551(0.51), 2.571 (0.94), 2.591 (0.45), 2.665 (0.43), 2.669 (0.58), 2.674(0.42), 2.760 (0.62), 2.784 (0.65), 2.800 (1.33), 2.817 (0.63), 2.838(0.57), 2.857 (1.06), 2.874 (0.74), 2.898 (0.48), 3.159 (2.70), 3.172(3.02), 3.188 (0.62), 3.197 (0.93), 3.213 (0.51), 3.220 (0.45), 3.421(1.07), 3.430 (1.46), 3.437 3-(3-fluoro-2-methylanilino)-2-(3- (1.91),3.454 (0.96), 4.097 (0.53), {[(25)-1-methylpyrrolidin-2- 4.109 (0.52),4.173 (0.99), 4.181 yl]methoxy}pyridin-4-yl)-1,5,6,7- (1.08), 4.199(1.20), 4.207 (1.12), tetrahydro-4H-pyrrolo[3,2-c]pyridin-4- 4.500(1.27), 4.504 (1.36), 4.525 one (1.15), 4.530 (1.14), 5.759 (4.64),6.076 (1.95), 6.096 (2.03), 6.464 (0.89), 6.487 (1.66), 6.509 (1.03),6.769 (0.61), 6.789 (1.30), 6.806 (1.25), 6.827 (0.54), 7.183 (1.99),7.237 (3.26), 7.250 (3.32), 7.376 (3.86), 7.929 (3.65), 7.941 (3.32),8.416 (5.15), 12.100 (1.91). LC-MS (method 2): Rt = 1.12 min; m/z = 450(M + H)+ 50

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.726 (1.09), 1.750 (1.22), 1.768(0.68), 1.826 (0.61), 1.847 (0.56), 1.861 (0.46), 1.905 (0.52), 1.941(0.78), 1.961 (0.74), 1.973 (0.50), 1.988 (0.51), 2.284 (0.59), 2.314(16.00), 2.327 (2.15), 2.351 (0.47), 2.518 (2.79), 2.523 (1.78), 2.556(0.55), 2.576 (1.00), 2.597 (0.50), 2.665 (0.58), 2.669 (0.77), 2.673(0.55), 2.728 (0.42), 2.764 (0.58), 2.787 (0.72), 2.805 (1.48), 2.822(0.84), 2.846 (1.37), 2.863 (0.79), 2.888 (0.88), 3.167 (0.58), 3.183(1.04), 3.200 (0.55), 3.410 (1.23), 3.426 (2.06), 3.440 (1.00), 3.667(1.18), 4.181 (1.06), 4.189 (1.11), 4.206 (1.27), 4.215 (1.15), 4.498(1.34), 4.503 (1.39), 4.524 (1.20), 4.529 (1.14), 6.271 (2.01), 6.274(2.01), 6.291 (2.14), 6.295 (2.01), 6.799 (1.85), 6.803 (1.88),3-[3-chloro-2- 6.819 (2.94), 6.823 (2.53), 6.879(difluoromethoxy)anilino]-2-(3-{[(2S)- (2.33), 6.900 (3.39), 6.920(1.38), 1-methylpyrrolidin-2- 7.039 (1.59), 7.150 (2.21), 7.224yl]methoxy}pyridin-4-yl)-1,5,6,7- (3.21), 7.351 (3.21), 7.363 (3.30),tetrahydro-4H-pyrrolo[3,2-c]pyridin-4- 7.408 (1.47), 7.502 (4.30), 7.975one (3.26), 7.988 (2.99), 8.444 (4.87), 12.155 (2.10). LC-MS (method 1):Rt = 0.58 min; m/z = 518 (M + H)+ 51

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.707 (0.61), 1.722 (1.21), 1.730(0.98), 1.743 (1.26), 1.751 (0.91), 1.763 (0.67), 1.780 (0.41), 1.811(0.57), 1.825 (0.51), 1.832 (0.54), 1.846 (0.43), 1.929 (0.79), 1.939(0.41), 1.949 (0.81), 1.960 (0.51), 1.979 (0.43), 2.145 (7.85), 2.193(0.49), 2.275 (0.53), 2.299 (1.71), 2.308 (16.00), 2.318 (1.75), 2.324(1.69), 2.332 (0.55), 2.342 (0.48), 2.518 (1.62), 2.523 (1.03), 2.539(0.91), 2.562 (0.93), 2.582 (0.44), 2.669 (0.43), 2.775 (0.54), 2.798(0.68), 2.815 (1.45), 2.833 (0.90), 2.854 (1.34), 2.871 (0.75), 2.895(0.51), 3.148 (0.51), 3.156 (0.57), 3.164 (0.67), 3.171 (1.01), 3.188(0.59), 3.195 (0.58), 3.413 (1.42), 3.419 (1.49), 3.436 (2.17), 3.448(1.11), 4.164 (1.01), 3-(3,5-difluoro-2-methylanilino)-2-(3- 4.173(1.08), 4.189 (1.23), 4.198 {[(2S)-1-methylpyrrolidin-2- (1.14), 4.467(1.24), 4.472 (1.33), yl]methoxy}pyridin-4-yl)-1,5,6,7- 4.492 (1.09),4.498 (1.07), 5.768 tetrahydro-4H-pyrrolo[3,2-c]pyridin-4- (1.11), 5.797(1.06), 6.375 (0.67), one 6.382 (0.73), 6.399 (1.09), 6.406 (1.14),6.423 (0.67), 6.430 (0.67), 7.154 (1.98), 7.297 (3.41), 7.309 (3.43),7.495 (2.87), 8.006 (4.18), 8.019 (3.76), 8.208 (0.81), 8.449 (5.62),12.118 (1.72). LC-MS (method 2): Rt = 0.54 min; m/z = 469 (M + H)+ 52

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.164 (0.91), 2.203 (0.93), 2.312(16.00), 2.322 (1.13), 2.327 (1.05), 2.332 (0.76), 2.362 (1.90), 2.369(8.88), 2.389 (0.73), 2.518 (2.96), 2.523 (1.98), 2.540 (0.69), 2.665(0.61), 2.669 (0.83), 2.673 (0.60), 2.708 (0.94), 2.721 (1.55), 2.734(1.06), 2.840 (0.91), 2.857 (1.95), 2.874 (1.02), 3.413 (0.78), 3.420(0.82), 3.430 (1.38), 3.436 (1.35), 3.447 (0.70), 3.453 (0.63), 4.383(1.01), 4.397 (1.57), 4.409 (1.01), 6.212 (0.97), 6.215 (0.95), 6.231(1.07), 6.235 (1.01), 6.732 (0.58), 6.736 (0.85), 6.752 (1.89), 6.756(1.55), 6.767 (1.35), 6.787 (1.41), 6.807 (0.48), 7.178 (1.26), 7.228(2.08), 7.240 (2.07), 7.379 (2.42), 7.934 (2.66), 7.948 (2.46), 8.164(2.48), 8.423 (3.57), 12.260 (1.18).3-(3-chloro-2-methylanilino)-2-{3[2- LC-MS (method 1): Rt = 0.69 min;(dimethylamino)ethoxy]pyridin-4-yl} m/z = 440 (M + H)+1,5,6,7-tetrahydro-4H-pyrrolo[3,2- c]pyridin-4-one 53

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.310 (16.00), 2.322 (0.79), 2.327(0.72), 2.332 (0.49), 2.518 (1.72), 2.523 (1.26), 2.669 (0.54), 2.713(0.88), 2.726 (1.44), 2.739 (0.92), 2.832 (0.92), 2.848 (2.01), 2.865(1.04), 3.408 (0.71), 3.414 (0.75), 3.425 (1.36), 3.430 (1.33), 3.442(0.66), 3.448 (0.60), 3.668 (0.53), 3.927 (9.60), 4.395 (1.03), 4.408(1.62), 4.421 (1.02), 6.005 (1.11), 6.025 (1.15), 6.487 (0.53), 6.490(0.55), 6.508 (0.74), 6.511 (0.75), 6.514 (0.63), 6.518 (0.57), 6.535(0.71), 6.538 (0.67), 6.625 (0.56), 6.641 (0.61), 6.646 (0.95), 6.661(0.95), 6.666 (0.47), 6.682 (0.42), 7.157 (1.25), 7.287 (2.16), 7.300(2.17), 7.572 (2.81), 7.969 (2.68), 7.982 (2.50), 8.442 (3.56), 12.276(1.10). 2-{3-[2-(dimethylamino)ethoxy]pyridin- LC-MS (method 2): Rt =1.02 min; 4-yl}-3-(3-fluoro-2-methoxyanilino)- m/z = 440 (M + H)+1,5,6,7-tetrahydro-4H-pyrrolo[3,2- c]pyridin-4-one 54

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (3.77), 1.172 (7.37), 1.190(3.66), 1.233 (0.81), 1.250 (0.66), 1.988 (14.22), 2.312 (15.54), 2.327(1.17), 2.332 (0.84), 2.518 (2.73), 2.523 (1.80), 2.664 (0.55), 2.669(0.77), 2.673 (0.57), 2.713 (0.99), 2.725 (1.57), 2.737 (1.00), 2.836(1.17), 2.853 (2.46), 2.869 (1.26), 3.222 (0.47), 3.410 (0.85), 3.415(0.91), 3.426 (1.65), 3.432 (1.64), 3.443 (0.81), 3.449 (0.74), 3.901(16.00), 4.000 (1.08), 4.017 (3.26), 4.035 (3.21), 4.053 (1.04), 4.398(1.28), 4.411 (1.99), 4.424 (1.24), 6.143 (1.41), 6.154 (1.54), 6.156(1.35), 6.167 (1.42), 6.690 (3.05), 6.693 (3.52), 6.704 (5.36), 7.158(1.60), 7.278 (2.59), 7.291 (2.63), 7.582 (3.49), 7.974 (3.17), 7.987(2.90), 8.447 (4.52), 12.301 (1.12).3-(3-chloro-2-methoxyanilino)-2-{3-[2- LC-MS (method 1): Rt = 0.64 min;(dimethylamino)ethoxy]pyridin-4-yl}- MS (ESIpos): m/z = 457 [M + H]⁺1,5,6,7-tetrahydro-4H-pyrrolo[3,2- c]pyridin-4-one 55

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.232 (1.99), 2.145 (4.77), 2.199(0.52), 2.222 (0.50), 2.227 (0.52), 2.235 (0.66), 2.242 (0.77), 2.303(16.00), 2.323 (0.62), 2.327 (0.73), 2.331 (0.59), 2.344 (1.24), 2.518(2.29), 2.523 (1.48), 2.665 (0.51), 2.669 (0.63), 2.673 (0.50), 2.696(1.02), 2.708 (1.60), 2.721 (1.06), 2.844 (0.90), 2.862 (1.96), 2.879(1.00), 3.413 (0.70), 3.419 (0.77), 3.430 (1.33), 3.436 (1.29), 3.447(0.65), 3.453 (0.61), 4.390 (1.06), 4.403 (1.62), 4.416 (1.08), 5.769(0.65), 5.798 (0.62), 6.370 (0.44), 6.376 (0.46), 6.394 (0.67), 6.400(0.68), 7.154 (1.19), 7.282 (1.96), 7.296 (1.99), 7.493 (1.77), 8.001(2.31), 8.014 (2.21), 8.463 (3.32), 12.343 (1.11). LC-MS (method 2): Rt= 0.67 min; 3-(3,5-difluoro-2-methylanilino)-2-{3- MS (ESIpos): m/z =442 [M + H]⁺ [2-(dimethylamino)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2- c]pyridin-4-one 56

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.122 (0.58), 2.202 (6.28), 2.223(1.15), 2.311 (16.00), 2.361 (1.79), 2.669 (1.15), 2.708 (1.72), 2.722(2.39), 2.734 (1.70), 2.838 (1.39), 2.855 (2.48), 2.872 (1.39), 3.420(1.25), 3.431 (1.86), 3.448 (1.01), 4 384 (1.37), 4.396 (2.03), 4.409(1.23), 5.758 (4.75), 6.078 (1.41), 6.098 (1.38), 6.453 (0.74), 6.474(1.20), 6.497 (0.71), 6.749 (0.50), 6.768 (0.99), 6.786 (0.90), 7.178(1.48), 7.228 (1.92), 7.241 (1.88), 7.357 (2.51), 7.927 (2.07), 7.939(1.86), 8.421 (3.30), 12.247 (1.38). LC-MS (method 2): Rt = 1.05 min;m/z = 424 (M + H)+ 2-{3-[2-(dimethylamino)ethoxy]pyridin-4-yl}-3-(3-fluoro-2-methylanilino)- 1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 57

¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.154 (1.07), 1.167 (16.00), 1.172(3.58), 1.190 (0.79), 1.983 (0.91), 1.988 (2.73), 2.000 (1.80), 2.017(0.87), 2.518 (1.31), 2.522 (0.79), 2.822 (0.75), 2.839 (1.62), 2.855(0.86), 3.117 (12.28), 3.385 (0.56), 3.391 (0.61), 3.403 (1.09), 3.408(1.07), 3.419 (0.55), 3.425 (0.50), 3.887 (7.39), 4.017 (0.56), 4.035(0.55), 4.172 (0.86), 4.190 (1.80), 4.207 (0.85), 5.964 (0.90), 5.985(0.94), 6.423 (0.42), 6.427 (0.45), 6.444 (0.59), 6.447 (0.63), 6.451(0.53), 6.454 (0.48), 6.471 (0.58), 6.474 (0.55), 6.564 (0.42), 6.579(0.48), 6.585 (0.76), 6.600 (0.74), 7.104 (1.05), 7.289 (1.72), 7.301(1.73), 7.483 (2.28), 8.028 (2.23), 8.0403-(3-fluoro-2-methoxyanilino)-2-[3-(3- (2.08), 8.360 (2.79), 11.215(1.05). methoxy-3-methylbutoxy)pyridin-4-yl] LC-MS (method 2): Rt = 1.07min; 1,5,6,7-tetrahydro-4H-pyrrolo[3,2- m/z = 469 (M + H)+c]pyridin-4-one 58

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.038 (2.31), 1.055 (5.14), 1.073(2.35), 1.284 (16.00), 2.522 (0.82), 2.798 (0.87), 2.815 (1.87), 2.833(0.97), 3.403 (0.67), 3.409 (0.75), 3.420 (1.96), 3.425 (1.43), 3.437(2.95), 3.455 (2.41), 3.472 (0.69), 3.909 (8.56), 4.176 (4.30), 6.003(1.00), 6.024 (1.04), 6.473 (0.45), 6.476 (0.46), 6.494 (0.65), 6.497(0.68), 6.504 (0.51), 6.521 (0.60), 6.525 (0.57), 6.619 (0.46), 6.634(0.54), 6.640 (0.83), 6.655 (0.81), 6.660 (0.42), 7.169 (1.17), 7.283(1.80), 7.295 (1.82), 7.480 (2.49), 8.010 (2.17), 8.022 (2.01), 8.398(3.13), 11.048 (1.23). LC-MS (method 2): Rt = 1.12 min; m/z = 469 (M +H)+ 2-[3-(2-ethoxy-2- methylpropoxy)pyridin-4-yl]-3-(3-fluoro-2-methoxyanilino)-1,5,6,7- tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 59

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.142 (0.87), 1.232 (1.27), 1.279(16.00), 2.084 (0.49), 2.327 (0.66), 2.331 (0.49), 2.518 (3.05), 2.522(1.84), 2.539 (0.59), 2.669 (0.67), 2.673 (0.49), 2.789 (0.86), 2.806(1.83), 2.824 (0.96), 3.397 (0.65), 3.403 (0.71), 3.414 (1.24), 3.419(1.22), 3.431 (0.62), 3.436 (0.55), 3.623 (0.64), 3.669 (0.81), 3.889(11.40), 4.082 (4.35), 5.535 (3.06), 6.161 (0.99), 6.169 (0.92), 6.178(0.99), 6.185 (1.00), 6.684 (0.48), 6.697 (3.97), 6.704 (1.95), 6.714(1.55), 7.151 (1.21), 7.255 (1.77), 7.267 (1.80), 7.523 (2.51), 7.992(2.08), 8.005 (1.92), 8.405 (3.07), 11.762 (1.21). LC-MS (method 2): Rt= 1.00 min; m/z = 457 (M + H)+ 3-(3-chloro-2-methoxyanilino)-2-[3-(2-hydroxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2- c]pyridin-4-one 60

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.132 (14.72), 1.232 (0.43), 2.074(0.69), 2.243 (16.00), 2.310 (0.26), 2.336 (0.48), 2.377 (8.32), 2.518(6.05), 2.522 (4.11), 2.673 (1.12), 2.678 (0.51), 2.846 (0.94), 2.863(1.99), 2.880 (1.02), 3.422 (0.74), 3.427 (0.79), 3.438 (1.38), 3.444(1.35), 3.455 (0.69), 4.222 (4.13), 6.211 (1.05), 6.228 (1.15), 6.748(0.66), 6.751 (0.79), 6.769 (1.61), 6.771 (1.45), 6.793 (1.17), 6.812(1.43), 6.832 (0.51), 7.188 (1.25), 7.2143-(3-chloro-2-methylanilino)-2-{3-[2- (1.99), 7.227 (2.04), 7.416(2.35), (dimethylamino)-2- 7.911 (2.19), 7.924 (1.99), 8.350methylpropoxy]pyridin-4-yl}-1,5,6,7- (3.16), 12.549 (1.22).tetrahydro-4H-pyrrolo[3,2-c]pyridin-4- LC-MS (method 2): Rt = 1.12 min;one m/z = 469 (M + H)+ 61

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.107 (0.61), 1.133 (14.44), 1.145(1.59), 1.154 (1.71), 1.173 (2.83), 1.190 (1.42), 1.988 (5.29), 2.210(4.86), 2.213 (4.85), 2.230 (1.49), 2.243 (16.00), 2.311 (1.09), 2.323(0.49), 2.327 (0.66), 2.332 (0.45), 2.518 (2.73), 2.523 (1.82), 2.540(5.80), 2.665 (0.47), 2.669 (0.63), 2.673 (0.47), 2.845 (0.85), 2.862(1.84), 2.879 (0.94), 3.429 (0.74), 3.439 (1.24), 3.445 (1.23), 3.456(0.63), 4.000 (0.44), 4.017 (1.19), 2-{3-[2-(dimethylamino)-2- 4.035(1.18), 4.221 (3.95), 5.758 methylpropoxy]pyridin-4-yl}-3-(3- (0.90),6.076 (1.11), 6.096 (1.16), fluoro-2-methylanilino)-1,5,6,7- 6.470(0.57), 6.491 (0.97), 6.513 tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-(0.57), 6.795 (0.74), 6.812 (0.75), one 7.187 (1.19), 7.218 (1.96),7.231 (2.02), 7.392 (2.22), 7.904 (2.56), 7.917 (2.44), 8.348 (3.36),12.535 (1.06). LC-MS (method 2): Rt = 1.18 min; m/z = 452 (M + H)+ 62

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.132 (14.72), 1.232 (0.43), 2.074(0.69), 2.243 (16.00), 2.310 (0.26), 2.336 (0.48), 2.377 (8.32), 2.518(6.05), 2.522 (4.11), 2.673 (1.12), 2.678 (0.51), 2.846 (0.94), 2.863(1.99), 2.880 (1.02), 3.422 (0.74), 3.427 (0.79), 3.438 (1.38), 3.444(1.35), 3.455 (0.69), 4.222 (4.13), 6.211 (1.05), 6.228 (1.15), 6.748(0.66), 6.751 (0.79), 6.769 (1.61), 6.771 (1.45), 6.793 (1.17), 6.812(1.43), 6.832 (0.51), 7.188 (1.25), 7.214 (1.99), 7.227 (2.04), 7.416(2.35), 7.911 (2.19), 7.924 (1.99), 8.350 (3.16), 12.549 (1.22). LC-MS(method 1): Rt = 0.70 min; m/z = 470 (M + H)+3-(3,5-difluoro-2-methylanilino)-2-{3- [2-(dimethylamino)-2-methylpropoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4- one 63

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.035 (0.89), 1.052 (1.76), 1.070(0.94), 1.526 (0.44), 1.558 (0.46), 1.651 (1.18), 1.677 (1.60), 1.750(0.52), 1.782 (0.46), 2.180 (0.55), 2.230 (9.58), 2.261 (0.84), 2.286(0.84), 2.318 (0.48), 2.322 (0.55), 2.326 (0.61), 2.332 (0.45), 2.518(2.59), 2.522 (1.77), 2.669 (0.54), 2.673 (0.41), 2.813 (0.59), 2.831(1.59), 2.848 (1.48), 2.865 (0.63), 3.031 (0.61), 3.061 (0.57), 3.285(0.41), 3.422 (0.92), 3.427 (0.82), 3.435 (1.56), 3.440 (1.38),3-(3-chloro-2-methoxyanilino)-2-(3-{[1- 3.452 (1.47), 3.457 (0.76),3.915 methylpiperidin-2-yl]methoxy}pyridin- (16.00), 4.356 (0.82), 4.3874-yl)-1,5,6,7-tetrahydro-4H- (1.74), 4.400 (1.34), 6.156 (1.37),pyrrolo[3,2-c]pyridin-4-one 6.168 (2.35), 6.180 (1.43), 6.721 (4.61),6.733 (3.82), 7.182 (1.65), 7.294 (2.71), 7.307 (2.71), 7.635 (3.42),7.957 (3.49), 7.970 (3.11), 8.379 (4.78), 12.282 (1.61). LC-MS (method2): Rt = 1.21 min; m/z = 496 (M + H)+ 64

¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.307 (16.00), 2.322 (0.41), 2.327(0.42), 2.518 (091), 2.523 (0.67), 2.705 (0.88), 2.718 (1.44), 2.731(0.90), 2.835 (0.87), 2.852 (1.89), 2.869 (0.98), 3.404 (0.64), 3.411(0.67), 3.422 (1 25), 3.427 (1.23), 3.438 (0-61), 3.444 (0.55), 3.672(0.57), 4.395 (0.98), 4.408 (1.53), 4.421 (0.96), 6.114 (1.08), 6.135(1.10), 6.569 (0.53), 6.572 (0.53), 6.590 (0.68), 6.594 (0.96), 6.597(0.58), 6.615 (0.62), 6.618 (0.58), 6.833 (0.46), 6.848 (0.52), 6.853(0.90), 6.869 (0.87), 6.874 (0.44), 7.032 (0.73), 7.141 (1.20), 7.218(1.46), 7.364 (2.07), 7.376 (2.12), 7.402 (0.67), 7.521 (2.63), 7.972(3.10), 7.984 (2.73), 8.452 (3.70), 12.341 (1.17). LC-MS (method 2): Rt= 1.05 min; m/z = 476 (M + H)+ 3-[2-(difluoromethoxy)-3-fluoroanilino]-2-{3-[2-(dimethylamino)ethoxy]pyridin- 4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one 65

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (2.91), 1.172 (5.85), 1.190(3.05), 1.686 (0.58), 1.699 (0.72), 1.705(1.17), 1.717 (1.57), 1.724(0.92), 1.730 (0.99), 1.737 (1.66), 1.749 (1.28), 1.769 (0.67), 1.987(11.68), 2.023 (0.74), 2.035 (0.81), 2.043 (1.08), 2.054 (1.48), 2.066(1.50), 2.074 (2.71), 2.088 (0.90), 2.096 (0.69), 2.108 (0.63), 2.145(0.49), 2.168 (16.00), 2.171 (15.82), 2.518 (5.02), 2.522 (3.16), 2.704(0.63), 2.718 (1.12), 2.732 (1.32), 2.740 (1.28), 2.755 (1.08), 2.768(0.54), 2.831 (3.00), 2.848 (6.41), 2.865 (3.45), 3.390 (2.31), 3.396(2.46), 3.407 (4.46), 3.412 (4.30), 3.424 (2.13), 3.430 (1.95), 3.592(1.37), 3.611 (3.43), 3.632 (3.63), 3.651 (1.61), 3.692 (1.12), 3.714(5.80), 3.719 (5.22), 3-(3-fluoro-2-methylanilino)-2-(3- 3.730 (8.02),3.741 (1.05), 3.754 {[oxolan-3-yl]methoxy}pyridin-4-yl)- (0.52), 3.837(2.73), 3.848 (1.64), 1,5,6,7-tetrahydro-4H-pyrrolo[3,2- 3.857 (2.67),3.869 (2.67), 3.878 c]pyridin-4-one (1.30), 3.890 (1.17), 3.999 (0.94),4.017 (2.71), 4.035 (2.69), 4.053 (0.96), 4.083 (1.41), 4.098 (1.59),4.106 (3.29), 4.122 (3.32), 4.130 (3.38), 4.144 (3.34), 4.154 (1.46),4.167 (1.30), 5.759 (2.73), 6.027 (3.92), 6.047 (3.99), 6.418 (1.97),6.440 (3.25), 6.462 (2.02), 6.717 (1.25), 6.737 (2.60), 6.755 (2.51),6.775 (1.05), 7.143 (3.90), 7.267 (7.19), 7.280 (7.75), 7.288 (8.13),7.983 (9.57), 7.996 (8.83), 8.351 (11.65), 11.108 (3.05). LC-MS (method2): Rt = 0.99 min; m/z = 437 (M + H)+ 66

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.667 (0.48), 1.676 (0.52), 1.681(0.43), 1.698 (0.60), 1.869 (0.83), 1.884 (1.47), 1.902 (1.17), 1.998(0.45), 2.011 (0.57), 2.025 (0.43), 2.030 (0.52), 2.044 (0.41), 2.518(2.49), 2.523 (1.71), 2.820 (0.81), 2.837 (1.69), 2.841 (1.61), 2.857(0.90), 3.398 (0.86), 3.404 (0.91), 3.415 (1.67), 3.421 (1.67), 3.432(0.76), 3.438 (0.72), 3.746 (0.47), 3.763 (0.90), 3.766 (0.93), 3.783(1.35), 3.800 (0.69), 3.831 (0.78), 3.847 (1.55), 3.871 (16.00), 3.884(0.62), 4.012 (0.79), 4.031 (1.07), 4.036 (1.05), 4.055 (0.95), 4.308(0.60), 4.316 (0.81), 4.326 (0.54), 4.334 (0.83), 4.352 (1.62), 4.360(0.69), 4.376 3-(3-chloro-2-methoxyanilino)-2-(3- (1.05), 4.385 (0.81),6.151 (1.40), {[(2S)-oxolan-2-yl]methoxy}pyridin-4- 6.160 (1.24), 6.166(1.48), 6.176 yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2- (1.45), 6.660(0.60), 6.670 (6.25), c]pyridin-4-one 6.680 (2.93), 6.686 (2.57), 7.138(1.55), 7.268 (2.12), 7.280 (2.16), 7.487 (3.42), 8.025 (1.83), 8.038(1.73), 8.425 (2.88), 11.255 (1.62). LC-MS (method 1): Rt = 0.97 min;m/z = 469 (M + H)+ 67

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.668 (0.49), 1.677 (0.53), 1.681(0.42), 1.698 (0.61), 1.869 (0.80), 1.885 (1.45), 1.902 (1.15), 1.998(0.42), 2.011 (0.55), 2.030 (0.51), 2.044 (0.42), 2.518 (3.33), 2.523(2.33), 2.823 (0.80), 2.837 (1.69), 2.841 (1.61), 2.857 (0.91), 3.397(0.81), 3.404 (0.85), 3.415 (1.65), 3.421 (1.66), 3.432 (0.74), 3.438(0.72), 3.746 (0.45), 3.763 (0.87), 3.766 (0.91), 3.783 (1.34), 3.800(0.66), 3.831 (0.70), 3.848 (1.53), 3.871 (16.00), 3.884 (0.58), 4.012(0.79), 4.030 (1.07), 4.036 (1.03), 4.055 (0.95), 4.308 (0.60), 4.316(0.81), 4.326 (0.51), 4.334 (0.81), 4.351 (1.64), 4.359 (0.69), 4.376(1.04), 4.384 (0.83), 3-(3-chloro-2-methoxyanilino)-2-(3- 6.152 (1.42),6.160 (1.25), 6.167 {[(2R)-oxolan-2-yl]methoxy}pyridin-4- (1.45), 6.176(1.49), 6.659 (0.61), 1)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2- 6.670(6.46), 6.679 (2.96), 6.686 c]pyridin-4-one (2.56), 7.138 (1.54), 7.266(2.56), 7.278 (2.59), 7.484 (3.40), 8.024 (3.29), 8.037 (3.01), 8.425(4.52), 11.252 (1.62). LC-MS (method 2): Rt = 1.07 min; m/z = 469 (M +H)+ 68

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.345 (0.39), 1.374 (0.52), 1.524(0.63), 1.550 (1.81), 1.629 (0.63), 1.660 (0.52), 1.837 (0.58), 2.327(0.73), 2.331 (0.55), 2.518 (3.33), 2.522 (2.04), 2.539 (0.76), 2.669(0.76), 2.673 (0.55), 2.843 (1.10), 2.860 (2.23), 2.877 (1.23), 3.405(0.89), 3.412 (0.94), 3.423 (1.73), 3.429 (1.70), 3.440 (0.81), 3.445(0.73), 3.528 (0.42), 3.555 (0.71), 3.674 (0.45), 3.818 (0.55), 3.840(0.42), 3.891 (16.00), 4.058 (1.47), 4.077 (1.41), 4.083 (1.60), 4.102(0.92), 4.330 (1.00), 4.337 (1.02), 4.356 (0.89), 4.363 (0.79), 6.141(1.44), 6.153 (2.41), 6.165 (1.44), 6.690 (3.74), 6.703 (4.27), 7.174(1.60), 7.274 (2.72), 7.286 (2.72), 7.562 (3.54), 8.005 (3.51),3-(3-chloro-2-methoxyanilino)-2-{3- 8.018 (3.17), 8.408 (4.79), 11.076[(oxan-2-yhmethoxy]pyridin-4-yl}- (1.75).1,5,6,7-tetrahydro-4H-pyrrolo[3,2- LC-MS (method 2): Rt = 1.15 min;c]pyridin-4-one m/z = 483 (M + H)+ 69

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.929 (0.40), 0.946 (0.68), 1.053(0.40), 1.173 (0.90), 1.232 (1.02), 1.305 (1.24), 1.334 (1.53), 1.504(1.98), 1.529 (5.26), 1.558 (1.87), 1.585 (2.26), 1.618 (1.64), 1.821(1.70), 1.906 (2.49), 1.988 (0.90), 2.075 (0.40), 2.454 (0.73), 2.518(16.00), 2.523 (9.95), 2.539 (2.88), 2.848 (3.34), 2.865 (7.18), 2.883(3.90), 3.416 (2.83), 3.428 (4.98), 3.434 (5.03), 3.445 (2.54), 3.480(1.36), 3.507 (2.37), 3.535 (1.07), 3.753 (1.58), 3.776 (1.13), 4.009(2.04), 4.026 (3.05), 4.044 (3.34), 4.052 (3.45), 4.070 (2.83), 4.175(3.00), 4.182 (3.11), 4.200 (2.32), 4.208 (2.09), 6.264 (4.35), 6.269(4.35), 6.283 (4.52), 6.288 (4.47), 6.857 (1.53), 6.862 (3.11),3-(2,3-dichloroanilino)-2-{3-[(oxan-2- 6.876 (9.10), 6.882 (9.50), 6.903yl)methoxy]pyridin-4-yl}-1,5,6,7- (6.61), 6.922 (2.09), 7.184 (4.81),tetrahydro-4H-pyrrolo[3,2-c]pyridin-4- 7.246 (4.75), 7.259 (4.86), 7.705one (10.63), 8.043 (3.17), 8.056 (3.05), 8.391 (5.09), 11.200 (5.03).LC-MS (method 2): Rt = 1.17 min; m/z = 487 (M + H)+ 70

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.602 (0.60), 1.620 (1.37), 1.639(1.76), 1.648 (1.55), 1.670 (1.78), 1.687 (0.92), 1.824 (1.01), 1.829(1.18), 1.844 (3.16), 1.860 (5.69), 1.877 (4.27), 1.898 (1.44), 1.907(1.07), 1.953 (1.10), 1.971 (1.55), 1.984 (1.76), 2.002 (1.65), 2.017(1.31), 2.035 (0.49), 2.518 (6.64), 2.523 (4.42), 2.827 (3.39), 2.845(7.04), 2.862 (4.06), 3.169 (0.92), 3.403 (2.88), 3.409 (3.07), 3.420(5.73), 3.426 (5.67), 3.437 (2.71), 3.443 (2.51), 3.716 (1.55), 3.732(3.01), 3.736 (3.16), 3.753 (4.60), 3.769 (2.32), 3.792 (2.62), 3.808(5.50), 3.826 (3.03), 3.829 (3.50), 3.846 (1.50), 3.991 (1.80), 4.010(3.63), 4.016 (3.65), 4.034 (2.38), 4.225 (3.14), 4.233 (4.98), 4.243(1.63), 4.256 (8.03), 4.273 3-(2,3-dichloroanilino)-2-(3-{[(2S)- (2.86),4.280 (1.93), 4.290 (0.92), oxolan-2-yl]methoxy}pyridin-4-yl)- 4.298(0.69), 6.276 (5.48), 6.280 1,5,6,7-tetrahydro-4H-pyrrolo[3,2- (5.58),6.295 (5.88), 6.300 (5.63), c]pyridin-4-one 6.831 (3.01), 6.836 (4.19),6.852 (9.99), 6.856 (8.59), 6.867 (7.75), 6.887 (8.42), 6.906 (2.86),7.149 (5.30), 7.240 (9.08), 7.253 (9.28), 7.602 (11.94), 8.059 (12.76),8.072 (11.79), 8.406 (16.00), 11.362 (5.56). LC-MS (method 2): Rt = 1.09min; m/z = 473 (M + H)+ 71

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.723 (1.04), 1.745 (1.14), 1.764(0.70), 1.906 (0.73), 1.933 (0.74), 1.953 (0.71), 1.987 (0.65), 2.074(2.50), 2.142 (0.92), 2.306 (16.00), 2.319 (1.54), 2.322 (1.55), 2.326(1.07), 2.331 (0.67), 2.518 (2.85), 2.522 (1.79), 2.565 (0.89), 2.669(0.68), 2.810 (1.36), 2.827 (0.66), 2.859 (1.20), 2.876 (0.76), 3.170(0.94), 3.382 (1.15), 3.398 (0.82), 3.419 (1.09), 3.435 (1.95), 3.451(0.95), 3.673 (0.65), 4.144 (0.99), 4.153 (1.10), 4.170 (1.21), 4.179(1.12), 4.453 (1.22), 4.458 (1.31), 4.479 (1.09), 4 484 (1.06), 6.280(2.02), 6.284 (2.14), 6.300 (2.22), 6.305 (2.10), 6.878 (1.34), 6.882(1.83), 6.898 (3.78), 6.903 (3.22), 6.915 (2.95), 6.934 (3.24), 6.954(1.09), 7.174 (2.00), 3-(2,3-dichloroanilino)-2-(3-{[(2S)-1- 7.244(3.51), 7.257 (3.62), 7.710 methylpyrrolidin-2-yl]methoxy}pyridin-(4.46), 7.995 (5.33), 8.007 (4.65), 4-yl)-1,5,6,7-tetrahydro-4H- 8.435(6.18), 12.152 (1.83). pyrrolo[3,2-c]pyridin-4-one LC-MS (method 2): Rt= 1.18 min; m/z = 486(M + H)+

Example 723-(3-fluoro-2-methoxyanilino)-2-[3-(2-hydroxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

N-(3-fluoro-2-methoxyphenyl)-4-({[3-(2-hydroxy-2-methylpropoxy)pyridin-4-yl]methyl}amino)-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide(88.0 mg, 185 μmol, intermediate 6-72) was solubilised in 1.8 mLmethanol, hydrogen peroxide (32 μl, 36% purity, 370 μmol) was added andthe mixture was stirred 2 h at 90° C. The reaction mixture wasconcentrated under reduced pressure, the residue was purified bypreparative HPLC to give 13 mg of the title compound (90% purity, 14%yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.146 (0.88), 1.231 (0.56), 1.249(0.79), 1.279 (16.00), 2.331 (0.45), 2.518 (2.35), 2.523 (1.54), 2.539(0.56), 2.673 (0.51), 2.786 (0.83), 2.803 (1.77), 2.819 (0.90), 3.396(0.64), 3.402 (0.68), 3.412 (1.18), 3.418 (1.15), 3.429 (0.58), 3.436(0.55), 3.693 (0.47), 3.712 (0.41), 3.916 (8.50), 3.925 (0.73), 4.080(4.47), 5.534 (2.61), 6.023 (0.98), 6.043 (1.00), 6.485 (0.49), 6.489(0.51), 6.506 (0.64), 6.509 (0.70), 6.512 (0.60), 6.516 (0.51), 6.533(0.58), 6.537 (0.55), 6.639 (0.47), 6.654 (0.55), 6.659 (0.81), 6.675(0.79), 6.680 (0.41), 7.152 (1.15), 7.262 (1.88), 7.275 (1.86), 7.516(2.44), 7.988 (2.37), 8.000 (2.20), 8.401 (3.31), 11.747 (1.13).

LC-MS (method 1): Rt=0.76 min; m/z=441 (M+H)+

The examples in Table 4 were prepared analogous to the preparation ofexample 72 starting from the corresponding intermediates by reactingwith the corresponding aldehydes.

TABLE 4 Example Structure Name Analytical Data 73

3-[2-(difluoromethoxy)-3-fluoroanilino]- 2-[3-(2-hydroxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one ¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.271 (16.00), 2.518 (0.96), 2.523 (0.68), 2.790 (0.80), 2.807(1.73), 2.824 (0.89), 3.392 (0.59), 3.398 (0.64), 3.409 (1.15), 3.415(1.11), 3.426 (0.56), 3.432 (0.51), 4.072 (4.19), 5.508 (3.71), 6.132(0.97), 6.153 (1.00), 6.564 (0.51), 6.567 (0.51), 6.585 (0.65), 6.589(0.88), 6.592 (0.54), 6.610 (0.55), 6.613 (0.52), 6.844 (0.42), 6.859(0.48), 6.865 (0.78), 6.880 (0.77), 6.885 (0.41), 7.020 (0.65), 7.133(1.10), 7.206 (1.29), 7.342 (1.56), 7.355 (1.57), 7.391 (0.61), 7.467(2.43), 7.992 (1.47), 8.005 (1.35), 8.408 (2.27), 11.774 (1.14). LC-MS(method 2): Rt = 0.98 min; m/z = 477 (M + H)+ 74

2-{3-[2-(dimethylamino)-2- methylpropoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one ¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.133 (14.39), 2.242 (16.00), 2.518 (1.56), 2.523 (1.15), 2.539(1.63), 2.838 (0.85), 2.855 (1.82), 2.872 (0.95), 3.417 (0.65), 3.423(0.70), 3.434 (1.25), 3.439 (1.24), 3.450 (0.63), 3.936 (8.83), 4.229(3.98), 6.004 (1.00), 6.024 (1.05), 6.504 (0.44), 6.507 (0.47), 6.525(0.65), 6.528 (0.68), 6.535 (0.52), 6.552 (0.61), 6.556 (0.59), 6.651(0.47), 6.666 (0.54), 6.672 (0.83), 6.687 (0.83), 6.692 (0.43), 7.167(1.20), 7.283 (1.76), 7.297 (1.81), 7.609 (2.51), 7.947 (1.80), 7.960(1.72), 8.368 (2.76), 12.556 (1.14). LC-MS (method 2): Rt = 1.15 min;m/z = 468 (M + H)+ 75

3-(3-fluoro-2-methoxyanilino)-2-{3-[2- methyl-2-(morpholin-4-yl)propoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one ¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.795 (0.94), 1.143 (0.73), 1.159 (16.00), 2.518 (2.68), 2.523(3.10), 2.534 (2.34), 2.539 (2.39), 2.544 (1.78), 2.874 (0.86), 2.891(1.84), 2.908 (0.95), 3.335 (2.93), 3.357 (1.14), 3.359 (1.04), 3.415(0.71), 3.421 (0.76), 3.432 (1.31), 3.437 (1.26), 3.448 (0.72), 3.454(0.61), 3.530 (1.92), 3.541 (2.44), 3.551 (1.83), 3.668 (2.11), 3.806(1.25), 3.809 (1.12), 3.913 (9.47), 3.915 (9.66), 3.936 (0.44), 3.939(0.46), 4.179 (3.96), 5.967 (1.10), 5.988 (1.15), 6.472 (0.53), 6.475(0.53), 6.493 (0.74), 6.496 (0.75), 6.499 (0.65), 6.502 (0.57), 6.520(0.70), 6.523 (0.66), 6.616 (0.52), 6.631 (0.59), 6.637 (0.94), 6.652(0.93), 6.658 (0.46), 7.194 (1.26), 7.307 (2.24), 7.319 (2.28), 7.471(2.87), 7.989 (2.88), 8.002 (2.59), 8.378 (3.48), 11.327 (1.31). LC-MS(method 2): Rt = 1.03 min; m/z = 510 M + H)+ 76

3-[2-(difluoromethoxy)-3-fluoroanilino]- 2-{3-[2-methyl-2-(morpholin-4-yl)propoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one ¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 1.153 (16.00), 2.073 (2.25), 2.331 (0.44), 2.518 (4.10), 2.523(3.49), 2.539 (4.26), 2.673 (0.44), 2.865 (0.86), 2.883 (1.83), 2.900(0.96), 3.407 (0.93), 3.412 (0.96), 3.423 (1.44), 3.429 (1.40), 3.440(0.78), 3.446 (0.70), 3.520 (1.90), 3.532 (2.45), 3.541 (1.91), 4.170(3.80), 6.084 (1.11), 6.105 (1.14), 6.548 (0.51), 6.552 (0.56), 6.569(0.69), 6.573 (0.97), 6.577 (0.62), 6.594 (0.63). 6.598 (0.59). 6.820(0.46), 6.835 (0.52), 6.841 (0.89), 6.856 (0.88), 6.861 (0.47), 6.877(0.41), 7.017 (0.74), 7.169 (1.27), 7.202 (1.51), 7.383 (1.63), 7.396(1.62), 7.424 (2.84), 7.995 (0.94), 8.008 (0.92), 8.386 (1.46), 11.417(1.35). LC-MS (method 2): Rt = 1.07 min; m/z = 546 (M + H)+

Example 773-(3-chloro-2-methylanilino)-2-(3-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

To a solution ofN-(3-chloro-2-methylphenyl)-4-{[(3-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1,2,5,6-tetrahydropyridine-3-carbothioamide(244 mg, 488 μmol) in 5.0 mL methanol was added trifluoroacetic acid (75μl, 980 μmol) and stirred for 5 min at rt. Then meta-chloroperoxybenzoicacid (168 mg, 976 μmol) was added and the mixture was stirred for 6 h at50° C. The reaction mixture was diluted with water and adjusted to pH 8with sodium hydroxide (1M in water). The aqueous layer was extractedwith ethyl acetate. The organic layer was filtered through awaterresistant filter, the filtrate was concentrated under reducedpressure and the residue was purified by preparative HPLC. The productfractions were combined and lyophilised to give 27.8 mg of the titlecompound (93% purity, 11% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.232 (0.56), 1.722 (0.44), 1.739(0.82), 1.758 (0.85), 1.779 (0.41), 1.946 (0.53), 1.966 (0.56), 2.317(11.38), 2.327 (1.84), 2.332 (1.50), 2.335 (1.26), 2.345 (1.02), 2.371(9.96), 2.387 (0.82), 2.518 (5.58), 2.523 (3.75), 2.539 (16.00), 2.567(0.63), 2.660 (0.46), 2.664 (1.02), 2.669 (1.45), 2.673 (1.04), 2.678(0.46), 2.786 (0.41), 2.803 (0.89), 2.819 (0.44), 2.857 (0.75), 2.874(0.48), 3.195 (0.60), 3.419 (0.70), 3.430 (0.97), 3.436 (1.28), 3.452(0.63), 4.171 (0.68), 4.180 (0.75), 4.197 (0.85), 4.206 (0.77), 4.497(0.87), 4.501 (0.92), 4.523 (0.77), 4.527 (0.75), 6.207 (1.16), 6.210(1.16), 6.226 (1.28), 6.230 (1.18), 6.743 (0.85), 6.747 (0.92), 6.763(2.01), 6.767 (1.72), 6.786 (1.43), 6.805 (1.64), 6.826 (0.58), 7.181(1.35), 7.235 (2.42), 7.247 (2.42), 7.397 (2.61), 7.936 (3.58), 7.949(3.19), 8.418 (4.28), 12.111 (1.35).

LC-MS (method 2): Rt=1.18 min; m/z=466 (M+H)+

The examples in Table 5 were prepared analogous to the preparation ofexample 77 starting from the corresponding intermediates by reactingwith the corresponding aldehydes.

TABLE 5 Example Structure Name Analytical Data 78

3-(2-bromo-3-chloroanilino)-2-[3-(2- methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2- c]pyridin-4-one ¹H-NMR (400 MHz,DMSO-d6) δ [ppm]: 1.263 (16.00), 2.518 (2.26), 2.523 (1.55), 2.539(0.92), 2.831 (0.74). 2.848 (1.61), 2.865 (0.83), 3.234 (13.85), 3.413(0.53), 3.418 (0.58). 3.429 (1.05), 3.436 (1.03), 3.446 (0.52), 3.452(0.47), 4.170 (4.06), 6.271 (1.02), 6.275 (1.07), 6.291 (1.06), 6.295(1.02), 6.881 (0.78), 6.884 (0.94), 6.900 (1.64), 6.904 (1.46), 6.936(1.21), 6.956 (1.64), 6.976 (0.62), 7.181 (1.81), 7.194 (2.70), 7.573(2.10), 8.016 (2.35), 8.029 (2.17), 8.423 (3.07), 11.262 (1.04). LC-MS(method 1): Rt = 0.93 min; m/z = 519 (M + H)+ 79

3-[3-chloro-2- (difluoromethoxy)anilino]-2-{3-[(oxolan-3-yl)methoxy]pyridin-4-yl}- 1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one ¹H NMR (400 MHz, CDCl₃): □ [ppm] = 2.01-2.17 (m, 1H),2.31- 2.44 (m, 1H), 2.83-3.10 (m, 3H), 3.54-3.66 (m, 2H), 3.68-3.91 (m2H), 4.17-4.30 (m, 2H), 4.33 (s, 2H), 5.17 (br s, 1H), 6.32-6.42 (m,1H), 6.60-7.02 (m, 3H), 7.18 (s, 1H), 7.57 (d, 1H), 8.05 (d, 1H), 8.28(s, 1H), 11.00 (br s, 1H). UPLC4-MS (Method 11): R_(t) = 3.28 min.,100%. MS (ESIpos): m/z = (M + H)⁺ 505 80

3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-pyrrolidin-2-yl]methoxy}pyridin- 4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.683(0.43), 1.768 (0.41), 1.780 (0.41), 1.853 (0.40), 1.904 (0.43), 2.518(3.67), 2.523 (2.51), 2.792 (0.48), 2.801 (0.86), 2.820 (0.92), 2.842(1.10), 2.860 (0.51), 2.881 (0.46), 2.896 (1.10), 2.912 (0.56), 2.936(0.73), 2.952 (0.65), 2.964 (0.44), 3.397 (0.84), 3.403 (0.87), 3.418(1.46), 3.431 (0.76), 3.437 (0.70), 3.604 (0.41), 3.655 (0.60), 3.871(0.51), 3.898 (16.00), 3.913 (0.52), 4.353 (0.83), 4.362 (0.87), 4.377(0.83), 4.387 (0.73), 6.164 (1.37), 6.174 (1.21), 6.178 (1.38), 6.188(1.38), 6.683 (0.49), 6.693 (5.70), 6.703 (2.84), 6.707 (2.59), 7.140(1.54), 7.270 (2.56), 7.283 (2.61), 7.577 (3.37), 7.970 (3.18), 7.983(2.81), 8.442 (4.73). LC-MS (method 1): Rt = 0.64 min; m/z = 468 (M +H)+ 81

3-[3-chloro-2- (difluoromethoxy)anilino]-2-{3-[2-(morpholin-4-yl)ethoxy]pyridin-4-yl}- 1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one ¹H NMR (400 MHz, CDCl₃): □ [ppm] = 2.54 (t, 4H), 2.86(t, 2H), 2.92 (t, 2H), 3.53-3.60 (m, 2H), 3.71 (t, 4H), 4.32 (t, 2H),5.22 (br s, 1H), 6.23-6.28 (m, 1H), 6.47- 6.89 (m, 3H), 7.17 (s, 1H),7.36 (d, 1H), 7.96 (d, 1H), 8.22 (s, 1H), 10.80 (s, 1H). UPLC4-MS(Method 11): R_(t) = 1.88 min., 100%. MS (ESIpos): m/z = (M + H)⁺ 534 82

3-[3-chloro-2- (difluoromethoxy)anilino)-2-{3-[(oxan-4-yl)-methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one ¹H NMR (400 MHz, CDCl₃): □[ppm] = 1.60-1.68 (m, 2H), 1.75- 1.86 (m, 2H), 2.19-2.38 (m, 1H),2.92-3.00 (m, 2H), 3.45-3.57 (t, 2H), 3.62-3.70 (m, 2H), 4.07-4.16 (m,2H), 4.19 (d, 2H), 5.32 (br s, 1H), 6.32-6.40 (m, 1H), 6.57-6.99 (m,3H), 7.22 (s, 1H), 7.43 (d, 1H), 8.08 (br s, 1H), 8.36 (br s, 1H), 9.85(br s, 1H). UPLC4-MS (Method 11): R_(t) = 3.29 min., 100%. MS (ESIpos):m/z = (M + H)⁺ 519

Example 833-[2-(difluoromethoxy)-3-fluoroanilino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one-hydrogenchloride (1/1) Salt

The hydrogen chloride salt of example 27 was prepared by treatment ofthe free base (example 27) with aqueous hydrogen chloride followed bylyophilization of the frozen mixture.

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.000 (3.64), 1.294 (16.00), 2.518(1.39), 2.522 (1.31), 2.525 (0.99), 2.911 (0.82), 2.924 (1.75), 2.938(0.90), 3.448 (0.66), 3.461 (1.21), 3.475 (0.58), 4.334 (4.09), 6.195(0.92), 6.213 (0.94), 6.710 (0.42), 6.712 (0.43), 6.726 (0.56), 6.729(0.82), 6.746 (0.50), 6.749 (0.47), 6.925 (0.43), 6.930 (0.74), 6.942(0.73), 7.086 (0.63), 7.233 (1.25), 7.381 (0.59), 7.418 (0.63), 7.664(1.69), 7.676 (1.73), 7.981 (1.70), 8.268 (1.33), 8.281 (1.27), 8.660(2.37), 11.410 (1.22).

Example 843-(3-fluoro-2-methoxyanilino)-2-{3-[2-(morpholin-4-yl)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

A solution of3-(3-fluoro-2-methoxyanilino)-2-(3-hydroxypyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one(intermediate 84-1, 150 mg, 407 μmol) in 2 mL dimethyl formamide wastreated with 4-(2-bromoethyl)morpholine (238 mg, 1.22 mmol) andpotassium carbonate (169 mg, 1.22 mmol) and the mixture was heatedovernight at 100° C. The reaction mixture was filtered and the filtratepurified by preparative HPLC to give 22.5 mg of the title compound (99%purity, 11% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.085 (0.62), 2.331 (1.10), 2.337(0.57), 2.518 (13.66), 2.523 (11.14), 2.674 (1.14), 2.678 (0.60), 2.791(1.36), 2.869 (1.57), 2.886 (3.34), 2.903 (1.86), 3.402 (1.45), 3.409(1.53), 3.419 (2.46), 3.425 (2.43), 3.436 (1.38), 3.442 (1.26), 3.587(4.01), 3.907 (16.00), 4.325 (1.43), 4.339 (2.74), 4.353 (1.55), 5.963(1.86), 5.966 (1.31), 5.984 (2.00), 6.456 (0.88), 6.460 (0.93), 6.477(1.26), 6.481 (1.29), 6.483 (1.17), 6.487 (1.07), 6.504 (1.24), 6.508(1.19), 6.590 (0.88), 6.605 (1.03), 6.611 (1.62), 6.626 (1.62), 6.631(0.88), 6.647 (0.74), 7.165 (2.17), 7.301 (3.48), 7.314 (3.60), 7.524(4.79), 8.009 (2.62), 8.021 (2.58), 8.400 (5.37), 11.142 (2.27).

LC-MS (method 2): Rt=0.94 min; m/z=482 (M+H)+

The examples in Table 6 were prepared analogous to the preparation ofexample 84 starting from the corresponding intermediates by reactingwith the corresponding aldehydes.

TABLE 6 Example Structure Name Analytical Data 85

2-{3-[2-(diethylamino)ethoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyanilino)- 1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.780 (0.42), 0.788(0.62), 0.806 (0.85), 0.824 (0.71), 0.833 (0.57), 0.844 (0.71), 0.851(0.59), 0.856 (0.59), 0.861 (0.54), 0.889 (0.42), 0.909 (0.62), 0.917(0.57), 0.928 (1.02), 0.935 (1.50), 0.946 (3.59), 0.964 (11.11), 0.982(16.00), 1.000 (6.19), 1.186 (0.62), 1.231 (0.54), 2.084 (4.01), 2.194(0.45), 2.318 (0.65), 2.322 (1.33), 2.326 (1.75), 2.331 (1.30), 2.336(0.68), 2.403 (0.51), 2.414 (0.54), 2.430 (0.68), 2.445 (0.88), 2.518(7.94), 2.523 (5.43), 2.616 (1.70), 2.634 (5.31), 2.652 (5.29), 2.665(2.09), 2.669 (3.39), 2.673 (2.12), 2.747 (1.07), 2.813 (1.64), 2.830(4.01), 2.834 (3.56), 2.848 (2.94), 3.088 (1.95), 3.391 (1.41), 3.402(1.84), 3.407 (1.84), 3.419 (2.26), 3.424 (2.15), 3.435 (1.13), 3.442(1.02), 3.920 (13.94), 3.941 (1.16), 3.951 (0.42), 4.349 (1.44), 4.362(2.66), 4.375 (1.47), 5.996 (1.67), 6.017 (1.72), 6.482 (0.79), 6.485(0.82), 6.502 (1.10), 6.506 (1.13), 6.509 (0.96), 6.513 (0.85), 6.530(1.02), 6.533 (0.96), 6.618 (0.82), 6.633 (0.93), 6.638 (1.41), 6.654(1.39), 6.659 (0.73), 6.675 (0.62), 7.181 (1.81), 7.293 (3.00), 7.306(3.05), 7.588 (4.07), 7.975 (3.79), 7.988 (3.56), 8.425 (5.00), 8.550(1.41), 11.757 (1.58). LC-MS (method 2): Rt = 0.99 min; m/z = 468 (M +H)+ 86

3-(3-fluoro-2-methoxyanilino)-2-{3- [(oxolan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2- c]pyridin-4-one ¹H-NMR (400 MHz,DMSO-d6) δ [ppm]: 1.232 (0.77), 1.649 (0.50), 1.661 (0.46), 1.669(0.64), 1.678 (0.72), 1.682 (0.60), 1.700 (0.83), 1.717 (0.43), 1.849(0.43), 1.856 (0.48), 1.873 (1.08), 1.886 (1.80), 1.904 (1.47), 1.909(0.91), 1.921 (0.50), 1.925 (0.46), 1.982 (0.44), 1.988 (0.52), 2.000(0.58), 2.012 (0.75), 2.031 (0.68), 2.045 (0.54), 2.331 (0.83), 2.518(4.57), 2.523 (2.90), 2.673 (0.87), 2.816 (1.06), 2.820 (1.04), 2.832(2.24), 2.838 (2.11), 2.850 (1.14), 2.854 (1.12), 3.396 (1.12), 3.402(1.20), 3.413 (2.26), 3.419 (2.24), 3.430 (1.03), 3.436 (0.95), 3.747(0.58), 3.764 (1.16), 3.767 (1.20), 3.783 (1.72), 3.801 (0.89), 3.833(0.93), 3.849 (1.99), 3.866 (1.18), 3.870 (1.33), 3.886 (0.75), 3.900(16.00), 4.004 (0.93), 4.022 (1.47), 4.028 (1.39), 4.047 (1.16), 4.303(0.44), 4.313 (0.83), 4.321 (1.16), 4.330 (0.70), 4.339 (1.18), 4.353(2.21), 4.360 (0.87), 4.377 (1.45), 4.385 (1.10), 6.011 (1.88), 6.031(1.92), 6.458 (0.93), 6.462 (0.91), 6.479 (1.26), 6.483 (1.26), 6.485(1.10), 6.489 (0.95), 6.506 (1.16), 6.510 (1.04), 6.608 (0.87), 6.623(1.01), 6.628 (1.57), 6.644 (1.55), 6.649 (0.75), 6.664 (0.68), 7.138(2.07), 7.269 (3.48), 7.282 (3.52), 7.481 (4.59), 8.019 (4.86), 8.032(4.47), 8.419 (6.31), 11.236 (2.13). LC-MS (method 2): Rt = 1.02 min;m/z = 453 (M + H)+ 87

2-[3-(2-tert-butoxyethoxy)pyridin-4-yl]-3-(3-chloro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one ¹H-NMR (400 MHz, DMSO-d6) δ[ppm]: 0.983 (0.44), 1.030 (0.40), 1.047 (0.44), 1.054 (0.44), 1.094(1.13), 1.112 (12.89), 1.146 (16.00), 1.162 (0.93), 2.447 (0.42), 2.518(1.11), 2.523 (0.73), 2.83 (0.78), 2.855 (0.45), 3.387 (0.51), 3.403(0.65), 3.409 (0.62), 3.510 (0.45), 3.672 (2.93), 3.711 (0.56), 3.720(0.69), 3.735 (0.53), 3.853 (0.60), 3.862 (5.49), 3.866 (2.20), 4.245(0.49), 4.258 (0.71), 4.268 (0.56), 6.126 (0.47), 6.137 (0.71), 6.150(0.53), 6.642 (1.22), 6.645 (1.33), 6.656 (1.65), 7.063 (0.65), 7.082(0.44), 7.116 (0.60), 7.122 (0.58), 7.278 (0.98), 7.291 (0.78), 7.467(1.09), 8.018 (0.85), 8.030 (0.82), 8.157 (0.42), 8.244 (0.64), 8.389(1.15). LC-MS (method 2): Rt = 1.03 min; m/z = 485 (M + H)+

Example 883-(3-fluoro-2-methoxyanilino)-2-{3-[(oxolan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one(enantiomer 1)

37 mg of the racemic title compound (example 86) was separated intoenantiomers by preparative chiral HPLC (method 8) to give enantiomer1(16.0 mg, example 88) and its enantiomer 2 (16.0 mg, example 89).

Analytical chiral HPLC (method 9): R_(t)=2.03 min

LC.MS (method 10): R, =0.74 min; MS (ESIpos): m/z=453 [M+H]⁺

optical rotation: [α]_(D) ²⁰=0.7°+/−2.06° (c=1.00; methanol)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.232 (1.61), 1.649 (0.49), 1.662(0.45), 1.669 (0.64), 1.678 (0.73), 1.683 (0.60), 1.695 (0.49), 1.700(0.84), 1.717 (0.47), 1.857 (0.45), 1.866 (0.99), 1.872 (1.07), 1.887(1.80), 1.903 (1.50), 1.908 (0.92), 1.921 (0.54), 1.925 (0.52), 1.983(0.45), 2.000 (0.60), 2.012 (0.75), 2.027 (0.58), 2.031 (0.69), 2.045(0.56), 2.336 (0.41), 2.518 (4.81), 2.523 (3.37), 2.816 (1.03), 2.820(1.03), 2.833 (2.26), 2.838 (2.13), 2.850 (1.14), 2.854 (1.14), 3.396(1.12), 3.403 (1.20), 3.413 (2.30), 3.420 (2.28), 3.430 (1.03), 3.437(0.97), 3.747 (0.60), 3.764 (1.16), 3.767 (1.22), 3.784 (1.76), 3.802(0.90), 3.833 (0.97), 3.850 (2.08), 3.866 (1.46), 3.870 (1.40), 3.886(0.75), 3.900 (16.00), 4.004 (0.97), 4.022 (1.48), 4.028 (1.44), 4.047(1.16), 4.303 (0.41), 4.313 (0.82), 4.321 (1.12), 4.331 (0.67), 4.339(1.18), 4.354 (2.23), 4.361 (0.86), 4.377 (1.48), 4.385 (1.12), 6.011(1.89), 6.032 (1.93), 6.458 (0.90), 6.462 (0.94), 6.479 (1.27), 6.483(1.29), 6.485 (1.07), 6.489 (0.99), 6.506 (1.20), 6.510 (1.12), 6.608(0.90), 6.623 (1.01), 6.628 (1.63), 6.644 (1.59), 6.649 (0.79), 6.665(0.71), 7.138 (2.08), 7.270 (2.21), 7.282 (2.26), 7.481 (4.75), 8.020(1.35), 8.033 (1.31), 8.420 (2.15), 11.235 (2.15).

Example 893-(3-fluoro-2-methoxyanilino)-2-{3-[(oxolan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one(enantiomer 2)

Analytical chiral HPLC (Method 9): R_(t)=4.04 min.

LC.MS (method 10): R, =0.74 min; MS (ESIpos): m/z=453 [M+H]⁺

optical rotation: [α]_(D) ²⁰=−1.1°+/−2.17° (c=1.00; methanol)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.155 (0.64), 1.232 (1.55), 1.650(0.51), 1.661 (0.49), 1.669 (0.66), 1.678 (0.75), 1.682 (0.62), 1.695(0.53), 1.700 (0.84), 1.717 (0.44), 1.849 (0.46), 1.857 (0.49), 1.873(1.11), 1.886 (1.84), 1.904 (1.50), 1.921 (0.53), 1.925 (0.49), 1.982(0.46), 2.000 (0.62), 2.012 (0.77), 2.031 (0.71), 2.045 (0.58), 2.331(0.97), 2.336 (0.44), 2.518 (5.58), 2.523 (3.43), 2.673 (1.00), 2.678(0.44), 2.816 (1.06), 2.820 (1.06), 2.832 (2.24), 2.838 (2.10), 2.850(1.17), 2.854 (1.13), 3.396 (1.15), 3.402 (1.24), 3.413 (2.30), 3.419(2.28), 3.430 (1.06), 3.436 (1.00), 3.747 (0.60), 3.764 (1.17), 3.767(1.22), 3.783 (1.70), 3.801 (0.89), 3.833 (0.95), 3.849 (2.01), 3.866(1.24), 3.870 (1.35), 3.886 (0.75), 3.900 (16.00), 4.004 (0.93), 4.022(1.44), 4.028 (1.37), 4.047 (1.15), 4.303 (0.44), 4.313 (0.84), 4.321(1.17), 4.330 (0.71), 4.339 (1.20), 4.353 (2.21), 4.360 (0.86), 4.377(1.42), 4.385 (1.08), 6.011 (1.86), 6.031 (1.95), 6.458 (0.91), 6.462(0.93), 6.479 (1.24), 6.483 (1.28), 6.485 (1.11), 6.489 (0.97), 6.506(1.15), 6.510 (1.06), 6.608 (0.86), 6.623 (1.02), 6.628 (1.55), 6.644(1.55), 6.649 (0.77), 6.664 (0.66), 7.138 (2.06), 7.269 (2.17), 7.282(2.21), 7.481 (4.54), 8.019 (1.35), 8.032 (1.31), 8.420 (2.15), 11.236(2.12).

Example 903-(3-fluoro-2-methoxyanilino)-2-(3-{[1-methylpiperidin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

To a solution of3-(3-fluoro-2-methoxyanilino)-2-(3-hydroxypyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one(intermediate 84-1, 163 mg, 441 μmol) in 1 ml. DMF,2-(bromomethyl)-1-methylpiperidine-hydrogen bromide (1/1) (181 mg, 662μmol) and potassium carbonate (183 mg, 1.323 mmol) were added and heatedfor 2.5 h at 60° C. The solvent was evaporated and the residue waspurified by preparative HPLC to give 6.2 mg of the title compound (90%purity, 3% yield).

LC-MS (method 2): R, =0.97 min; MS (ESIpos): m/z=480 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: −0.007 (1.96), 0.006 (1.81), 1.361(0.76), 1.538 (0.80), 1.564 (0.76), 1.674 (1.81), 1.756 (0.87), 1.786(0.73), 2.127 (0.94), 2.164 (0.87), 2.235 (12.41), 2.261 (1.05), 2.274(0.73), 2.287 (1.23), 2.307 (0.83), 2.323 (1.67), 2.361 (1.89), 2.365(2.39), 2.368 (1.89), 2.372 (1.27), 2.518 (6.86), 2.522 (6.24), 2.525(4.90), 2.543 (0.69), 2.631 (0.83), 2.635 (1.71), 2.638 (2.25), 2.642(1.67), 2.645 (0.80), 2.811 (0.80), 2.825 (1.41), 2.837 (1.16), 2.851(1.20), 2.863 (0.83), 3.036 (0.91), 3.060 (0.73), 3.246 (0.80), 3.425(0.80), 3.439 (1.52), 3.444 (1.27), 3.452 (1.41), 3.946 (16.00), 4.384(1.89), 4.395 (1.52), 4.402 (1.52), 6.024 (1.71), 6.041 (1.74), 6.517(0.76), 6.519 (0.87), 6.533 (1.05), 6.536 (1.12), 6.541 (0.91), 6.555(0.98), 6.558 (0.94), 6.661 (0.80), 6.673 (0.87), 6.677 (1.38), 6.689(1.34), 6.694 (0.69), 7.177 (2.14), 7.308 (3.27), 7.319 (3.27), 7.621(3.99), 7.951 (4.17), 7.962 (4.03), 8.313 (3.30), 8.373 (5.66), 8.566(1.31), 12.255 (1.85).

Example 912-[3-(2-tert-butoxyethoxy)pyridin-4-yl]-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

3-(3-fluoro-2-methoxyanilino)-2-(3-hydroxypyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one(Intermediate 84-1, 88.2 mg, 239 μmol) and2-tributylphosphoranylidene)acetonitrile (82 μl, 310 μmol) were solvedin 4.0 ml. toluene, 2-tert-butoxyethan-1-ol (38 μl, 290 μmol) was addedand the mixture was stirred 2.5 h at 120° C. The reaction mixture wascooled down to rt and concentrated under reduced pressure. The residuewas purified by preparative HPLC to give 38.8 mg of the yellow titlecompound (purity, yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.861 (0.75), 0.879 (1.91), 0.896(1.01), 1.149 (16.00), 1.359 (0.46), 1.374 (0.45), 2.819 (0.46), 2.836(0.99), 2.853 (0.52), 3.403 (0.66), 3.408 (0.67), 3.718 (0.56), 3.729(0.85), 3.742 (0.64), 3.894 (4.70), 4.238 (0.60), 4.251 (0.84), 4.262(0.58), 5.982 (0.52), 6.003 (0.55), 6.596 (0.42), 6.611 (0.40), 7.125(0.63), 7.283 (0.89), 7.295 (0.90), 7.473 (1.30), 8.017 (0.92), 8.029(0.89), 8.384 (1.51), 10.945 (0.69).

LC-MS (method 2): R, =1.10 min; MS (ESIpos): m/z=469 [M+H]⁺

Example 923-(3-fluoro-2-methoxyanilino)-2-{3-[(2R)-2-methoxypropoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

3-(3-fluoro-2-methoxyanilino)-2-(3-hydroxypyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one(Intermediate 84-1, 155 mg, 421 μmol) and(tributyl-lambda⁵-phosphanylidene)acetonitrile (200 μl, 760 μmol) weresolved in 5.0 ml. 1,4-dioxane, (2R)-2-methoxypropan-1-ol [CAS 6131-59-5](56.9 mg, 631 μmol) was added and the mixture was stirred for 1 h at150° C. in the microwave. The reaction mixture was cooled down to rt andconcentrated under reduced pressure. The residue was purified bypreparative HPLC to give 34.0 mg of the title compound (95% purity, 17%yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.194 (9.65), 1.209 (9.72), 2.518(3.12), 2.522 (2.02), 2.539 (0.66), 2.830 (0.99), 2.834 (1.00), 2.846(2.23), 2.852 (2.20), 2.864 (1.17), 2.869 (1.17), 3.330 (4.42), 3.353(1.93), 3.397 (1.31), 3.404 (1.34), 3.415 (2.46), 3.421 (2.40), 3.432(1.14), 3.438 (1.06), 3.820 (0.68), 3.829 (0.80), 3.836 (1.09), 3.845(1.17), 3.852 (0.77), 3.861 (0.77), 3.905 (16.00), 4.091 (1.30), 4.107(1.23), 4.117 (1.70), 4.133 (1.53), 4.240 (1.58), 4.249 (1.62), 4.266(1.21), 4.275 (1.13), 5.997 (1.90), 6.017 (1.95), 6.464 (0.92), 6.468(0.93), 6.485 (1.27), 6.488 (1.27), 6.492 (1.07), 6.495 (0.98), 6.513(1.21), 6.516 (1.12), 6.610 (0.92), 6.625 (1.02), 6.630 (1.66), 6.646(1.63), 6.651 (0.80), 6.666 (0.71), 7.146 (2.09), 7.281 (3.24), 7.294(3.26), 7.513 (4.80), 8.020 (2.37), 8.033 (2.22), 8.161 (1.55), 8.407(3.61), 11.074 (2.12).

LC-MS (method 1): R_(t)=0.78 min; MS (ESIpos): m/z=441 [M+H]⁺

Example 933-(3-fluoro-2-methoxyanilino)-2-{3-[(1-phenylpropan-2-yl)oxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

3-(3-fluoro-2-methoxyanilino)-2-(3-hydroxypyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one(intermediate 84-1, 157 mg, 425 μmol) and 2-(tributylphosphoranylidene)acetonitrile (330 μl, 1.3 mmol) were solved in 4.0 ml. 1,4-dioxane underargon atmosphere. 1-phenylpropan-2-ol (116 mg, 851 μmol) were added andstirred overnight at 80° C. The reaction mixture was cooled down to rtand concentrated under reduced pressure. The residue was purified bypreparative HPLC to give 16.5 mg of the title compound (95% purity, 8%yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.008 (0.74), 1.023 (0.69), 1.232(0.61), 1.259 (8.00), 1.273 (7.82), 1.654 (0.61), 2.332 (1.12), 2.337(0.48), 2.518 (5.92), 2.523 (3.96), 2.674 (1.12), 2.679 (0.56), 2.823(0.97), 2.838 (1.09), 2.858 (1.85), 2.861 (1.80), 2.873 (2.01), 2.878(3.10), 2.896 (1.75), 2.910 (0.56), 2.921 (0.51), 3.069 (1.14), 3.086(1.19), 3.103 (0.99), 3.120 (0.97), 3.415 (1.12), 3.422 (1.22), 3.432(2.18), 3.439 (2.23), 3.450 (1.02), 3.456 (0.91), 3.870 (16.00), 4.756(0.58), 4.772 (1.22), 4.787 (1.22), 4.802 (0.58), 5.878 (1.80), 5.899(1.88), 6.389 (0.76), 6.392 (0.86), 6.409 (1.37), 6.413 (1.35), 6.420(0.89), 6.437 (1.32), 6.441 (1.22), 6.473 (1.02), 6.488 (1.12), 6.494(1.60), 6.509 (1.55), 6.514 (0.79), 6.530 (0.61), 7.101 (2.16), 7.135(0.69), 7.143 (0.63), 7.150 (1.19), 7.155 (0.99), 7.159 (0.81), 7.166(1.27), 7.171 (1.40), 7.185 (1.65), 7.189 (1.19), 7.199 (15.29), 7.206(4.11), 7.212 (2.97), 7.214 (3.05), 7.232 (0.61), 7.235 (0.43), 7.277(3.63), 7.289 (3.63), 7.399 (4.88), 7.998 (4.22), 8.010 (3.73), 8.153(1.19), 8.325 (5.13), 10.977 (2.36).

LC-MS (method 2): R_(t)=1.17 min; MS (ESIpos): m/z=487 [M+H]⁺

Example 942-fluoro-6-({2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-3-yl}amino)benzonitrile

3-(2-bromo-3-fluoroanilino)-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one(example 37, 87.0 mg, 173 μmol), palladium(pi-cinnamyl) chloride dimer(4.48 mg, 8.64 μmol) and Xphos (20.6 mg, 43.2 μmol) were solubilised in1.6 ml. isopropanol, N,N-diisopropylethylamine (60 μl, 350 μmol) wasadded and the mixture was degassed with argon and heated up to 80° C.Then a solution of 2-hydroxy-2-methylpropanenitrile (70 μl, 760 μmol) in990 μL iso-propanol was added carefully under argon and the mixture wasstirred 2.5 h at 80° C. The reaction mixture was quenched with asaturated aqueous solution sodium bicarbonate and stirred for severalminutes. The aqueous phase was extracted with dichloromethane threetimes. The combined organic layers were filtered using a waterresistantfilter and the filtrate was concentrated under reduced pressure. Theresidue was purified by preparative HPLC to give 3.4 mg of the titlecompound (95% purity, 4% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.107 (10.64), 1.263 (16.00), 2.326(0.47), 2.522 (1.58), 2.669 (0.47), 2.829 (0.84), 2.846 (1.79), 2.863(0.93), 3.233 (11.99), 3.413 (0.68), 3.419 (0.74), 3.429 (1.24), 3.435(1.21), 3.447 (0.63), 3.452 (0.56), 4.165 (4.38), 4.194 (0.98), 6.152(1.02), 6.173 (1.05), 6.605 (0.51), 6.608 (0.51), 6.626 (1.00), 6.629(0.98), 6.647 (0.56), 6.650 (0.54), 6.927 (0.42), 6.944 (0.54), 6.948(0.82), 6.965 (0.81), 6.968 (0.49), 7.179 (1.82), 7.191 (2.75), 7.542(2.30), 8.006 (1.73), 8.018 (1.63), 8.417 (2.66), 11.251 (1.17).

LC-MS (method 1): R_(t)=0.93 min; MS (ESIpos): m/z=450 [M+H]⁺

Example 953-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

A solution of3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-pyrrolidin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one(example 80, 36.0 mg, 76.9 μmol) in 2 mL anhydrous DMF was treated withtriethylamine (64.3 μl, 0.462 mmol) followed by 2,2,2-trifluoroethyltrifluoromethanesulfonate (49.9 μl, 0.346 mmol) and the mixture wasstirred at rt overnight. The reaction mixture was filtrated and thefiltrate was purified by preparative. HPLC The product rich fractionspooled and acetonitrile was evaporated off. The water phase wasextracted with ethyl acetate two times. The combined organic phases werewashed with brine, dried, using a waterresistant filter and the filtratewas concentrated under reduced pressure to give 7.9 mg of the titlecompound (95% purity, 18% yield).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (5.15), 1.172 (9.05), 1.189(4.35), 1.231 (0.97), 1.759 (0.66), 1.771 (0.81), 1.781 (0.69), 1.790(0.78), 1.814 (0.41), 1.824 (0.42), 1.975 (0.45), 1.987 (16.00), 2.518(0.95), 2.522 (0.58), 2.588 (0.45), 2.606 (0.50), 2.766 (0.83), 2.783(1.61), 2.800 (0.92), 3.151 (0.71), 3.164 (0.49), 3.174 (0.48), 3.188(0.44), 3.274 (0.45), 3.399 (0.65), 3.407 (0.87), 3.413 (1.04), 3.429(0.54), 3.661 (0.54), 3.879 (11.65), 3.999 (1.17), 4.017 (3.53), 4.035(3.50), 4.053 (1.18), 4.186 (0.43), 4.201 (0.74), 4.212 (0.67), 4.249(0.72), 4.258 (0.76), 4.274 (0.43), 6.116 (1.03), 6.123 (0.98), 6.132(0.96), 6.140 (1.04), 6.655 (1.79), 6.664 (2.22), 6.671 (4.25), 6.683(0.45), 7.146 (1.20), 7.281 (1.84), 7.294 (1.86), 7.529 (2.57), 8.007(2.18), 8.020 (2.02), 8.372 (2.89), 11.149 (1.28).

LC-MS (method 2): R_(t)=1.20 min; MS (ESIpos): m/z=550 [M+H]⁺

Example 963-(3-chloro-4-fluoro-2-methoxyanilino)-2-(3-{2-[methyl(2,2,2-trifluoroethyl)amino]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one

Using an analogous method as described for Example 95 formicacid-3-(3-chloro-4-fluoro-2-methoxyanilino)-2-{3-[2-(methylamino)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one(1/1) (intermediate 96-2, 27.0 mg, 53.4 μmol) as the starting material,the title compound was prepared 3 mg (85% purity, 9% yield).

LC-MS (method 2): R_(t)=1.17 min; MS (ESIpos): m/z=542 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.849 (1.48), 0.866 (3.59), 0.885(3.18), 0.904 (5.77), 0.923 (2.62), 1.231 (2.57), 1.279 (1.43), 1.288(1.65), 1.299 (1.82), 1.315 (1.47), 1.337 (1.00), 1.353 (1.10), 1.373(0.99), 1.391 (1.18), 1.411 (2.91), 1.426 (0.83), 1.430 (0.87), 1.683(0.51), 1.698 (0.61), 1.713 (0.44), 2.331 (0.42), 2.518 (2.65), 2.523(2.60), 2.529 (8.46), 2.673 (0.43), 2.808 (1.15), 2.825 (2.44), 2.843(1.28), 3.018 (1.14), 3.031 (2.14), 3.044 (1.16), 3.307 (0.82), 3.358(1.88), 3.384 (0.76), 3.390 (0.97), 3.396 (0.98), 3.407 (1.70), 3.413(1.66), 3.424 (0.85), 3.430 (0.76), 3.918 (16.00), 4.227 (1.48), 4.233(1.61), 4.241 (1.59), 4.247 (1.48), 4.309 (1.26), 4.322 (2.33), 4.335(1.20), 6.091 (1.21), 6.105 (1.27), 6.114 (1.36), 6.128 (1.32), 6.756(1.29), 6.778 (2.41), 6.801 (1.20), 7.155 (1.61), 7.281 (0.89), 7.293(0.91), 7.421 (3.43), 8.025 (0.51), 8.087 (10.06), 8.398 (0.59), 11.154(1.72).

Experimental Section—Biological Assays

The pharmacological activity of the compounds according to the inventioncan be assessed using in vitro- and/or in vivo-assays, as known to theperson skilled in the art. The following examples describe thebiological activity of the compounds according to the invention, withoutthe invention being limited to said examples.

Example compounds according to the invention were tested in selectedbiological assays one or more times. When tested more than once, dataare reported as either average values or as median values, wherein

-   -   the average value, also referred to as the arithmetic mean        value, represents the sum of the values obtained divided by the        number of times tested, and    -   the median value represents the middle number of the group of        values when ranked in ascending or descending order. If the        number of values in the data set is odd, the median is the        middle value. If the number of values in the data set is even,        the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more thanonce, data from biological assays represent average values or medianvalues calculated utilizing data sets obtained from testing of one ormore synthetic batch.

The in vitro activity of the compounds of the present invention can bedemonstrated in the following assays:

Expression and Purification of the EGFR Proteins Used in the BiochemicalKinase Assays

The different EGFR proteins used in the biochemical kinase activityinhibition assays were generated inhouse by expression in insect cellsusing Baculo Virus system and subsequent purification as described inthe following paragraphs.

Expression Constructs:

The cDNAs encoding the various protein sequences from human EGFR(UniProt Accession No. P00533) were optimized for expression ineukaryotic cells and synthesized by the GeneArt Technology at LifeTechnologies. These DNA sequences encoded the following sequence:

Construct EGFR #1 amino acid R669 to A1210

Construct EGFR #2 amino acid R669 to A1210 and the insertion of theamino acids sequence ASV between V769 and D770

Construct EGFR #3 amino acid R669 to A1210 and the insertion of theamino acids sequence SVD between D770 and N771

Additionally all constructs EGFR #1 to #3 encoded: at the N-terminus aTEV (Tobacco etch virus) protease cleavage site (DYDIPTTENLYFQG (SEQ IDNO: 8)), at the C-terminus two stop codons and additionally 5′ and 3′att-DNA sequences for Gateway Cloning.

Each of the four EFGR constructs was subcloned using the GatewayTechnology into the Destination vector pD-Ins1. The vector pD-Ins1 is aBaculovirus transfer vector (based on vector pVL1393, Pharmingen) whichprovides a N-terminal fusion of a GST-tag to the integrated geneconstruct. The respective transfer vectors were termed pD-Ins1_EGFR #1,pD-Ins1_EGFR #2, pD-Ins1_EGFR #3.

EGFR amino acid sequences: GST-EGFR #1 (Wild Type) - SEQ ID NO: 1MSPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKSDPITSLYKKAGSDYDIPTTTENLYFQGRRRHIVRKRTLRRLLQERELVEPLTPSGEAPNQALLRILKETEFKKIKVLGSGAFGTVYKGLWIPEGEKVKIPVAIKELREATSPKANKEILDEAYVMASVDNPHVCRLLGICLTSTVQLITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAARNVLVKTPQHVKITDFGLAKLLGAEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSYGVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDVYMIMVKCWMIDADSRPKFRELIIEFSKMARDPQRYLVIQGDERMHLPSPTDSNFYRALMDEEDMDDVVDADEYLIPQQGFFSSPSTSRTPLLSSLSATSNNSTVACIDRNGLQSCPIKEDSFLQRYSSDPTGALTEDSIDDTFLPVPEYINQSVPKRPAGSVQNPVYHNQPLNPAPSRDPHYQDPHSTAVGNPEYLNTVQPTCVNSTFDSPAHWAQKGSHQISLDNPDYQQDFFPKEAKPNGIFKGSTAENAEYLRVAPQS SEFIGAGST-EGFR #2 (ASV between V769 and D770) SEQ ID NO: 2MSPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKSDPITSLYKKAGSDYDIPTTTENLYFQGRRRHIVRKRTLRRLLQERELVEPLTPSGEAPNQALLRILKETEFKKIKVLGSGAFGTVYKGLWIPEGEKVKIPVAIKELREATSPKANKEILDEAYVMASVDASVNPHVCRLLGICLTSTVQLITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAARNVLVKTPQHVKITDFGLAKLLGAEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSYGVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDVYMIMVKCWMIDADSRPKFRELIIEFSKMARDPQRYLVIQGDERMHLPSPTDSNFYRALMDEEDMDDVVDADEYLIPQQGFFSSPSTSRTPLLSSLSATSNNSTVACIDRNGLQSCPIKEDSFLQRYSSDPTGALTEDSIDDTFLPVPEYINQSVPKRPAGSVQNPVYHNQPLNPAPSRDPHYQDPHSTAVGNPEYLNTVQPTCVNSTFDSPAHWAQKGSHQISLDNPDYQQDFFPKEAKPNGIFKGSTAENAEYLRVAP QSSEFIGAGST-EGFR #3 (SVD between D770 and N771) - SEQ ID NO: 3MSPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKSDPITSLYKKAGSDYDIPTTTENLYFQGRRRHIVRKRTLRRLLQERELVEPLTPSGEAPNQALLRILKETEFKKIKVLGSGAFGTVYKGLWIPEGEKVKIPVAIKELREATSPKANKEILDEAYVMASVDSVDNPHVCRLLGICLTSTVQLITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAARNVLVKTPQHVKITDFGLAKLLGAEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSYGVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDVYMIMVKCWMIDADSRPKFRELIIEFSKMARDPQRYLVIQGDERMHLPSPTDSNFYRALMDEEDMDDVVDADEYLIPQQGFFSSPSTSRTPLLSSLSATSNNSTVACIDRNGLQSCPIKEDSFLQRYSSDPTGALTEDSIDDTFLPVPEYINQSVPKRPAGSVQNPVYHNQPLNPAPSRDPHYQDPHSTAVGNPEYLNTVQPTCVNSTFDSPAHWAQKGSHQISLDNPDYQQDFFPKEAKPNGIFKGSTAENAEYLRVAP QSSEFIGAGeneration of Recombinant Baculovirus:

In separate approaches each of the three transfer vectors wasco-transfected in Sf9 cells with Baculovirus DNA (Flashbac Gold DNA,Oxford Expression Technologies) using Fugene HD (Roche). After 5 daysthe supernatant of the transfected cells containing the recombinantBaculovirus encoding the various EGFR proteins was used for furtherinfection of Sf9 cells for virus amplification whereby the virus titerwas monitored using qPCR.

EGFR Expression in Sf9 Cells Using Bioreactor:

Sf9 cells cultured (Insect-xpress medium, Lonza, 27° C.) in aWave-bioreactor with a disposable culture bag were infected at a celldensity of 106 cells/ml with one of the recombinant baculovirus stocksat a multiplicity of infection of 1 and incubated for 48 h. Subsequentlythe cells were harvested by centrifugation and the cell pellet frozen at−80° C.

Purification of the GST-EGFR Fusion Proteins:

Purification of the GST-EGFR fusion proteins was achieved by affinitychromatography using Glutathion Sepharose 4B matrix (GE Healthcare LifeSciences).

The pelleted cells (from 4 I cell culture) were resuspended inLysis-Buffer (50 mM HEPES pH 7.4, 150 mM NaCl, 5% Glycerol, 1 mM MgCl2,1 mM MnCl2, 0.5 mM Na3V04) and lysed by a freeze-thaw cycle followed byan incubation on ice for 60 min. The supernatant was centrifuged at4000×g for 30 min. at 4° C. The supernatant was than incubated withGlutathion Sepharose 4B matrix (in a glass bottle rotating for 16 h, at4° C.) for binding of the GST EGFR fusion protein, rinsed withWash-Buffer and finally the bound protein was eluted usingElusion-Buffer (Lysis Buffer plus 25 mM Glutathione) and shock frozenwith liquid nitrogen.

WT-EGFR Kinase Assay

Inhibitory activity of compounds of the present invention againstwild-type Epidermal Growth Factor Receptor (EGFR) was quantifiedemploying the TR-FRET based EGFR assay as described in the followingparagraphs.

Recombinant fusion protein of N-terminal Glutathion-S-Transferase (GST)and a fragment of human EGFR (amino acids R669 to A1210), expressed inSf9 insect cells and purified via affinity chromatography usingGlutathion Sepharose as described above, was used as a kinase. Assubstrate for the kinase reaction the biotinylated peptidebiotin-Ahx-AEEEEYFELVAKKK—SEQ ID NO: 4 (C-terminus in amide form) wasused, which can be purchased e.g. from the company Biosynthan GmbH(Berlin-Buch, Germany).

For the assay 50 nl of a 100 fold concentrated solution of the testcompound in DMSO was pipetted into either a black low volume 384 wellmicrotiter plate or a black 1536 well microtiter plate (both GreinerBio-One, Frickenhausen, Germany), 2 μl of a solution of EGFR in aqueousassay buffer [50 mM Hepes pH 7.0, 10 mM MgCl2, 1 mM dithiothreitol, 0.5mM EGTA, 0.3 mM activated sodium ortho-vanadate, 0.005% (w/v) bovineserum albumin, 0.005% (v/v) Tween-20] were added and the mixture wasincubated for 15 min at 22° C. to allow pre binding of the testcompounds to the enzyme before the start of the kinase reaction. Thenthe kinase reaction was started by the addition of 3 μL of a solution ofadenosine tri phosphate (ATP, 3.33 mM=>final cone, in the 5 μL assayvolume is 2 mM) and substrate (1.67 μM=>final cone, in the 5 μL assayvolume is 1 μM) in assay buffer and the resulting mixture was incubatedfor a reaction time of 30 min at 22° C. The concentration of EGFR wasadjusted depending of the activity of the enzyme lot and was chosenappropriate to have the assay in the linear range, typical concentrationwas 7.6 pg/μl. The reaction was stopped by the addition of 3 μl of asolution of HTRF detection reagents (83.3 nM streptavidine-XL665 [CisbioBioassays, Codolet, France] and 1.67 nM PT66-Tb-Cryptate, anterbium-cryptate labelled anti-phospho-tyrosine antibody from CisbioBioassays [instead of the PT66 Tb cryptate PT66 Eu Chelate from PerkinElmer can also be used]) in an aqueous EDTA-solution (133.3 mM EDTA,0.2% (w/v) bovine serum albumin in 50 mM HEPES pH 7.5).

The resulting mixture was incubated 1 h at 22° C. to allow the bindingof the biotinylated phosphorylated peptide to the streptavidine-XL665and the PT66-Tb-Cryptate. Subsequently the amount of phosphorylatedsubstrate was evaluated by measurement of the resonance energy transferfrom the PT66-Tb-Cryptate to the streptavidine-XL665. Therefore, thefluorescence emissions at 620 nm and 665 nm after excitation at 337 nmwere measured in a HTRF reader, e.g. a Pherastar (BMG Labtechnologies,Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of theemissions at 665 nm and at 622 nm was taken as the measure for theamount of phosphorylated substrate. The data were normalised (enzymereaction without inhibitor=0% inhibition, all other assay components butno enzyme=100% inhibition). Usually the test compounds were tested onthe same microtiterplate in 11 different concentrations in the range of20 μM to 0.07 nM (20 μM, 5.7 μM, 1.6 μM, 0.47 μM, 0.13 μM, 38 nM, 11 nM,3.1 nM, 0.9 nM, 0.25 nM and 0.07 nM, the dilution series preparedseparately before the assay on the level of the 100-fold concentratedsolutions in DMSO by serial dilutions, exact concentrations may varydepending pipettors used) in duplicate values for each concentration andIC50 values were calculated using Genedata Screener™ software.

Exon 20-Mutant-EGFR(D770_N771insSVD) Kinase Assay

Inhibitory activity of compounds of the present invention against anEpidermal Growth Factor Receptor (EGFR) with an insertion of the aminoacids sequence SVD between D770 and N771 was quantified employing theTR-FRET based kinase activity assay as described in the followingparagraphs.

A recombinant fusion protein of N-terminal Glutathion-S-Transferase(GST) and a fragment of human EGFR variant (amino acids R669 to A1210with insertion of the amino acids sequence SVD between D770 and N771(“EGFR ins SVD”), expressed in Sf9 insect cells and purified viaaffinity chromatography using Glutathion Sepharose as described above,was used as a kinase. As substrate for the kinase reaction thebiotinylated peptide biotin-Ahx-AEEEEYFELVAKKK—SEQ ID NO: 4 (C-terminusin amide form) was used which can be purchased e.g. form the companyBiosynthan GmbH (Berlin-Buch, Germany).

For the assay 50 nl of a 100-fold concentrated solution of the testcompound in DMSO was pipetted into either a black low volume 384 wellmicrotiter plate or a black 1536 well microtiter plate (both GreinerBio-One, Frickenhausen, Germany), 2 μl of a solution of EGFR in aqueousassay buffer [50 mM Hepes pH 7.0, 10 mM MgCl2, 1 mM dithiothreitol, 0.5mM EGTA, 0.3 mM activated sodium ortho-vanadate, 0.005% (w/v) bovineserum albumin, 0.005% (v/v) Tween-20] were added and the mixture wasincubated for 15 min at 22° C. to allow pre binding of the testcompounds to the enzyme before the start of the kinase reaction. Thenthe kinase reaction was started by the addition of 3 μL of a solution ofadenosine tri phosphate (ATP, 3.33 mM=>final cone, in the 5 μL assayvolume is 2 mM) and substrate (1.67 μM=>final cone, in the 5 μL assayvolume is 1 μM) in assay buffer and the resulting mixture was incubatedfor a reaction time of 30 min at 22° C. The concentration of EGFR wasadjusted depending of the activity of the enzyme lot and was chosenappropriate to have the assay in the linear range, typical concentrationwas 15 pg/μl. The reaction was stopped by the addition of 3 μl of asolution of HTRF detection reagents (83.3 nM streptavidine-XL665 [CisbioBioassays, Codolet, France] and 1.67 nM PT66-Tb-Cryptate, aterbium-cryptate labelled anti-phospho-tyrosine antibody from CisbioBioassays [instead of the PT66 Tb cryptate PT66 Eu Chelate from PerkinElmer can also be used]) in an aqueous EDTA-solution (133.3 mM EDTA,0.2% (w/v) bovine serum albumin in 50 mM HEPES pH 7.5).

The resulting mixture was incubated 1 h at 22° C. to allow the bindingof the biotinylated phosphorylated peptide to the streptavidine-XL665and the PT66-Tb-Cryptate. Subsequently the amount of phosphorylatedsubstrate was evaluated by measurement of the resonance energy transferfrom the PT66-Tb-Cryptate to the streptavidine-XL665. Therefore, thefluorescence emissions at 620 nm and 665 nm after excitation at 337 nmwere measured in a HTRF reader, e.g. a Pherastar (BMG Labtechnologies,Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of theemissions at 665 nm and at 622 nm was taken as the measure for theamount of phosphorylated substrate. The data were normalised (enzymereaction without inhibitor=0% inhibition, all other assay components butno enzyme=100% inhibition). Usually the test compounds were tested onthe same microtiterplate in 11 different concentrations in the range of20 μM to 0.07 nM (20 μM, 5.7 μM, 1.6 μM, 0.47 μM, 0.13 μM, 38 nM, 11 nM,3.1 nM, 0.9 nM, 0.25 nM and 0.07 nM, the dilution series preparedseparately before the assay on the level of the 100 fold concentratedsolutions in DMSO by serial dilutions, exact concentrations may varydepending pipettors used) in duplicate values for each concentration andIC50 values were calculated using Genedata Screener™ software.

Exon 20-Mutant-EGFR(V769_D770insASV) Kinase Assay

Inhibitory activity of compounds of the present invention against anEpidermal Growth Factor Receptor (EGFR) with an insertion of the aminoacids sequence ASV between V769 and D770 was quantified employing theTR-FRET based kinase activity assay as described in the followingparagraphs.

A recombinant fusion protein of N-terminal Glutathion-S-Transferase(GST) and a fragment of human EGFR variant (amino acids R669 to A1210with insertion of the amino acids sequence ASV between V769 and D770;(“EGFR ins ASV”), expressed in Sf9 insect cells and purified viaaffinity chromatography using Glutathion Sepharose as described above,was used as kinase. As substrate for the kinase reaction thebiotinylated peptide biotin-Ahx-AEEEEYFELVAKKK—SEQ ID NO: 4 (C-terminusin amide form) was used which can be purchased e.g. form the companyBiosynthan GmbH (Berlin-Buch, Germany).

For the assay 50 nl of a 100-fold concentrated solution of the testcompound in DMSO was pipetted into either a black low volume 384wellmicrotiter plate or a black 1536 well microtiter plate (both GreinerBio-One, Frickenhausen, Germany), 2 μl of a solution of EGFR in aqueousassay buffer [50 mM Hepes pH 7.0, 10 mM MgCl2, 1 mM dithiothreitol, 0.5mM EGTA, 0.3 mM activated sodium ortho-vanadate, 0.005% (w/v) bovineserum albumin, 0.005% (v/v) Tween-20] were added and the mixture wasincubated for 15 min at 22° C. to allow pre binding of the testcompounds to the enzyme before the start of the kinase reaction. Thenthe kinase reaction was started by the addition of 3 μL of a solution ofadenosine tri phosphate (ATP, 3.33 mM=>final cone, in the 5 μL assayvolume is 2 mM) and substrate (1.67 μM=>final cone, in the 5 μL assayvolume is 1 μM) in assay buffer and the resulting mixture was incubatedfor a reaction time of 30 min at 22° C. The concentration of EGFR wasadjusted depending of the activity of the enzyme lot and was chosenappropriate to have the assay in the linear range, typical concentrationwas 2.5 pg/μl. The reaction was stopped by the addition of 3 μl of asolution of HTRF detection reagents (83.3 nM streptavidine-XL665 [CisbioBioassays, Codolet, France] and 1.67 nM PT66-Tb-Cryptate, anterbium-cryptate labelled anti-phospho-tyrosine antibody from CisbioBioassays [instead of the PT66 Tb cryptate PT66 Eu Chelate from PerkinElmer can also be used]) in an aqueous EDTA-solution (133.3 mM EDTA,0.2% (w/v) bovine serum albumin in 50 mM HEPES pH 7.5).

The resulting mixture was incubated 1 h at 22° C. to allow the bindingof the biotinylated phosphorylated peptide to the streptavidine-XL665and the PT66-Tb-Cryptate. Subsequently the amount of phosphorylatedsubstrate was evaluated by measurement of the resonance energy transferfrom the PT66-Tb-Cryptate to the streptavidine-XL665. Therefore, thefluorescence emissions at 620 nm and 665 nm after excitation at 337 nmwere measured in a HTRF reader, e.g. a Pherastar (BMG Labtechnologies,Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of theemissions at 665 nm and at 622 nm was taken as the measure for theamount of phosphorylated substrate. The data were normalised (enzymereaction without inhibitor=0% inhibition, all other assay components butno enzyme=100% inhibition). Usually the test compounds were tested onthe same microtiterplate in 11 different concentrations in the range of20 μM to 0.07 nM (20 μM, 5.7 μM, 1.6 μM, 0.47 μM, 0.13 μM, 38 nM, 11 nM,3.1 nM, 0.9 nM, 0.25 nM and 0.07 nM, the dilution series preparedseparately before the assay on the level of the 100-fold concentratedsolutions in DMSO by serial dilutions, exact concentrations may varydepending pipettors used) in duplicate values for each concentration andIC₅₀ values were calculated using Genedata Screener™ software and theresults for each EGFR assay are shown in Table 7.

TABLE 7 EGFR ins SVD EGFR ins ASV Example IC₅₀ IC₅₀ No. [mol/l] (mean)[mol] (mean) 1 7.79E−10 5.87E−9 2 3.99E−9 2.64E−8 3 2.80E−10 6.85E−9 4<7.2E−11 1.31E−10 5 1.56E−9 4.31E−9 6 <7.2E−11 2.12E−10 7 7.18E−10 — 83.10E−10 — 9 <7.2E−11 6.15E−9 10 <7.2E−11 — 11 2.20E−10 4.25E−9 128.57E−11 2.18E−10 13 4.41E−9 3.89E−8 14 2.66E−9 2.39E−8 15 4.89E−101.34E−9 16 1.38E−10 2.12E−10 17 1.13E−10 1.77E−10 18 1.20E−10 3.00E−1019 1.55E−10 2.39E−10 20 1.49E−10 3.22E−10 21 1.38E−10 2.13E−10 221.76E−10 3.09E−10 23 2.59E−10 3.42E−10 24 5.41E−10 6.34E−10 25 1.09E−92.93E−8 26 2.68E−10 9.43E−10 27 2.14E−9 7.09E−9 28 7.38E−10 2.69E−8 292.46E−10 6.08E−9 30 9.69E−11 2.09E−10 31 9.88E−11 1.61E−10Bub1 Kinase Assay

Bub1-inhibitory activities of compounds described in the presentinvention were quantified using a time-resolved fluorescence energytransfer (TR-FRET) kinase assay which measures phosphorylation of thesynthetic peptide Biotin-Ahx-VLLPKKSFAEPG—SEQ ID NO: 5 (C-terminus inamide form), purchased from e.g. Biosyntan (Berlin, Germany) by the(recombinant) catalytic domain of human Bub1 (amino acids 704-1085),expressed in Hi5 insect cells with an N-terminal His6-tag (SEQ ID NO: 9)and purified by affinity-(Ni-NTA) and size exclusion chromatography.

In a typical assay 11 different concentrations of each compound (0.1 nM,0.33 nM, 1.1 nM, 3.8 nM, 13 nM, 44 nM, 0.15 μM, 0.51 μM, 1.7 μM, 5.9 μMand 20 μM) were tested in duplicate within the same microtiter plate. Tothis end, 100-fold concentrated compound solutions (in DMSO) werepreviously prepared by serial dilution (1:3.4) of 2 mM stocks in a clearlow volume 384-well source microtiter plate (Greiner Bio-One,Frickenhausen, Germany), from which 50 nl of compounds were transferredinto a black low volume test microtiter plate from the same supplier.Subsequently, 2 μl of Bub1 (the final concentration of Bub1 was adjusteddepending on the activity of the enzyme lot in order to be within thelinear dynamic range of the assay: typically ˜ 200 ng/ml were used) inaqueous assay buffer [50 mM Tris/HCl pH 7.5, 10 mM magnesium chloride(MgCl2), 200 mM potassium chloride (KCl), 1.0 mM dithiothreitol (DTT),0.1 mM sodium ortho-vanadate, 1% (v/v) glycerol, 0.01% (w/v) bovineserum albumine (BSA), 0.005% (v/v) Triton X-100 (Sigma), 1× CompleteEDTA-free protease inhibitor mixture (Roche)] were added to thecompounds in the test plate and the mixture was incubated for 15 min at22° C. to allow pre-equilibration of the putative enzyme-inhibitorcomplexes before the start of the kinase reaction, which was initiatedby the addition of 3 μl 1.67-fold concentrated solution (in assaybuffer) of adenosine-tri-phosphate (ATP, 10 μM final concentration) andpeptide substrate (1 μM final concentration). The resulting mixture (5μl final volume) was incubated at 22° C. during 60 min., and thereaction was stopped by the addition of 5 μl of an aqueous EDTA-solution(50 mM EDTA, in 100 mM HEPES pH 7.5 and 0.2% (w/v) bovine serum albumin)which also contained the TR-FRET detection reagents (0.2 μMstreptavidin-XL665 [Cisbio Bioassays, Codolet, France] and 1 nManti-phosho-Serine antibody [Merck Millipore, cat. #35-002] and 0.4 nMLANCE EU-W1024 labeled anti-mouse IgG antibody [Perkin-Elmer, productno. AD0077, alternatively a Terbium-cryptate-labeled anti-mouse IgGantibody from Cisbio Bioassays can be used]). The stopped reactionmixture was further incubated 1 h at 22° C. in order to allow theformation of complexes between peptides and detection reagents.Subsequently, the amount of product was evaluated by measurement of theresonance energy transfer from the Eu-chelate-antibody complexrecognizing the Phosphoserine residue to the streptavidin-XL665 bound tothe biotin moiety of the peptide. To this end, the fluorescenceemissions at 620 nm and 665 nm after excitation at 330-350 nm weremeasured in a TR-FRET plate reader, e.g. a Rubystar or Pherastar (bothfrom BMG Labtechnologies, Offenburg, Germany) or a Viewlux(Perkin-Elmer) and the ratio of the emissions (665 nm/622 nm) was takenas indicator for the amount of phosphorylated substrate. The data werenormalised using two sets of control wells for high-(=enzyme reactionwithout inhibitor=0%=Minimum inhibition) and low-(=all assay componentswithout enzyme=100%=Maximum inhibition) Bub1 activity. IC₅₀ values werecalculated by fitting the normalized inhibition data to a 4-parameterlogistic equation (Minimum, Maximum, IC50, Hill;Y=Max+(Min−Max)/(1+(X/IC50)Hill)). The IC₅₀ values for the examples areshown in Table 8.

TABLE 8 Bub1 kinase assay Example IC₅₀ No. [mol/l] (mean) 1 1.45E−8 24.41E−8 3 4.76E−8 4 1.25E−8 5 3.24E−8 6 2.69E−8 7 3.97E−7 8 6.58E−8 92.72E−8 10 1.24E−8 11 1.92E−7 12 — 13 3.50E−7 14 7.04E−7 15 1.87E−7 161.45E−7 17 5.51E−8 18 3.75E−7 19 1.49E−7 20 6.74E−8 21 — 22 1.11E−7 236.73E−8 24 — 25 2.28E−7 26 8.58E−8 27 7.01E−8 28 5.65E−7 29 2.01E−7 303.23E−7 31 2.65E−7Bub1 High ATP Kinase Assay

Bub1-inhibitory activity of compounds of the present invention at a highATP concentration was quantified employing the Bub1 TR-FRET high ATPkinase assay as described in the following paragraphs.

N-terminally His₆-tagged (SEQ ID NO: 9) recombinant catalytic domain ofhuman Bub1 (amino acids 704-1085), expressed in insect cells (Hi5) andpurified by Ni-NTA affinity chromatography and subsequent size exclusionchromatography, was used as enzyme. As substrate for the kinase reactionthe biotinylated peptide biotin-Ahx-VLLPKKSFAEPG—SEQ ID NO: 5(C-terminus in amid form) was used which can be purchased e.g. form thecompany Biosyntan (Berlin, Germany).

For the assay 50 nl of a 100-fold concentrated solution of the testcompound in DMSO was pipetted into either a black low volume 384wellmicrotiter plate or a black 1536well microtiter plate (both GreinerBio-One, Frickenhausen, Germany), 3 μl of a solution ofadenosine-tri-phosphate (ATP, 3.33 mM=>final cone, in the 5 μl assayvolume is 2 mM) and substrate (1.67 μM=>final cone, in the 5 μl assayvolume is 1 μM) in aqueous assay buffer [50 mM Tris/HCl pH 7.5, 10 mMmagnesium chloride (MgCl₂), 200 mM potassium chloride (KOI), 1.0 mMdithiothreitol (DTT), 0.1 mM sodium ortho-vanadate, 1% (v/v) glycerol,0.01% (w/v) bovine serum albumine (BSA), 0.005% (v/v) Triton X-100(Sigma), 1× Complete EDTA-free protease inhibitor mixture (Roche)] wereadded. Then the kinase reaction was started by the addition of 2 μl of asolution of Bub1 in assay buffer and the resulting mixture was incubatedfor a reaction time of 60 min at 22° C. The concentration of Bub1 wasadjusted depending of the activity of the enzyme lot and was chosenappropriate to have the assay in the linear range, a typicalconcentration is about 200 ng/ml. The reaction was stopped by theaddition of 3 μl of a solution of TR-FRET detection reagents (0.167 μMstreptavidine-XL665 [Cisbio Bioassays, Codolet, France] and 1.67 nManti-phosho-Serine antibody [Merck Millipore, cat. #35-002] and 0.67 nMLANCE EU-W1024 labeled anti-mouse IgG antibody [Perkin-Elmer, productno. AD0077, as an alternative a Terbium-cryptate-labeled anti-mouse IgGantibody from Cisbio Bioassays can be used]) in an aqueous EDTA-solution(83.3 mM EDTA, 0.2% (w/v) bovine serum albumin in 100 mM HEPES pH 7.5).

The resulting mixture was incubated 1 h at 22° C. to allow the formationof complex between the phosphorylated biotinylated peptide and thedetection reagents. Subsequently the amount of phosphorylated substratewas evaluated by measurement of the resonance energy transfer from theEu-chelate to the streptavidin-XL. Therefore, the fluorescence emissionsat 620 nm and 665 nm after excitation at 350 nm was measured in aTR-FRET reader, e.g. a Pherastar or Pherastar FS (both from BMGLabtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). Theratio of the emissions at 665 nm and at 622 nm was taken as the measurefor the amount of phosphorylated substrate. The data were normalised(enzyme reaction without inhibitor=0% inhibition, all other assaycomponents but no enzyme=100% inhibition). Usually the test compoundswere tested on the same microtiterplate in 11 different concentrationsin the range of 20 μM to 0.7 nM (20 μM, 5.7 μM, 1.6 μM, 0.47 μM, 0.13μM, 38 nM, 11 nM, 3.1 nM, 0.9 nM, 0.25 nM and 0.07 nM, the dilutionseries prepared separately before the assay on the level of the 100 foldconcentrated solutions in DMSO by serial dilutions, exact concentrationsmay vary depending pipettors used) in duplicate values for eachconcentration and IC₅₀ values were calculated by a 4 parameter fit.

Table 9 shows the results of the inhibition in mutant EGFR biochemicalassay.

TABLE 9 mutEGFR (D770_N771insSVD) kinase assay Example IC₅₀ No. [mol/l]1 7.79E−10 2 3.99E−9 3 2.80E−10 4 <7.25E−11 5 1.56E−9 6 <7.25E−11<7.25E−11 1.04E−10 9.49E−11 7 1.13E−9 8 3.24E−10 9 3.60E−10 3.88E−107.76E−11 <7.25E−11 1.00E−10 9.62E−11 1.96E−10 2.06E−10 10 <7.25E−11<7.25E−11 1.33E−10 <7.25E−11 <7.25E−11 11 2.92E−10 12 8.57E−11 134.41E−9 14 2.66E−9 15 4.89E−10 16 1.58E−10 17 1.13E−10 18 1.53E−10 191.48E−10 20 1.49E−10 21 1.47E−10 22 1.76E−10 23 1.91E−10 24 5.41E−10 251.26E−9 26 4.15E−10 27 2.14E−9 28 5.40E−10 29 2.45E−10 30 1.09E−10 311.93E−10 32 7.60E−11 <7.25E−11 33 2.25E−10 3.34E−10 1.66E−10 1.61E−102.75E−10 <7.25E−11 34 9.46E−11 35 1.85E−10 36 1.94E−10 37 1.20E−107.95E−11 1.07E−10 9.58E−11 <7.25E−11 <7.25E−11 38 1.30E−10 39 1.04E−1040 9.94E−11 41 1.24E−10 42 1.90E−10 43 1.00E−10 44 9.22E−11 <7.25E−11 453.19E−10 46 9.12E−11 47 1.69E−10 48 3.58E−10 49 5.18E−10 50 1.26E−9 517.32E−10 52 5.50E−10 53 3.32E−10 54 9.12E−10 55 4.65E−10 56 5.62E−10 572.28E−10 58 1.13E−10 59 <7.25E−11 60 6.95E−10 61 1.12E−9 62 6.63E−10 635.09E−10 64 4.43E−10 65 5.22E−10 66 9.32E−11 67 9.08E−11 68 1.15E−10 691.06E−10 70 9.18E−11 71 2.58E−10 72 1.44E−10 73 1.67E−10 74 8.65E−10 759.03E−10 76 8.45E−10 77 7.27E−10 78 <7.25E−11 7.36E−11 79 2.42E−10 805.03E−10 81 4.41E−10 82 3.99E−10 83 1.67E−10 84 2.23E−10 85 2.00E−9 861.22E−10 87 2.04E−10 88 8.88E−11 89 1.08E−10 90 6.90E−10 91 1.35E−10 921.18E−10 93 2.77E−10 94 2.28E−10 95 1.87E−10 96 3.05E−10Cellular Data Description (WT, insSVD, Ins ASV)

293T cells from ATCC were transfected with pBABEpuro expressionconstructs for WT EGFR or EGFR-insSVD and pCL-Eco packaging vector usingFugene-6 transfection reagent from Promega. Plates were incubated at 37°C. for 48 h. Retrovirus was harvested by filtering the media supernatantthrough a 0.45 μm filter.

Ba/F3 cells purchased from DSMZ were grown in RPMI+10% FBS+10 ng/mL IL-3and infected with filtered retroviral supernatant at a 1:2 dilution.Polybrene was added to a concentration of 8 μg/mL, plates were spun for90 min, and incubated overnight at 37° C. 2 μg/mL puromycin was added tothe infected cells 24 h after infection and cells were continually grownin the presence of puromycin and 10 ng/mL IL-3. Following stablyexpressing Ba/F3 cell lines were generated: Ba/F3-EGFR-WT,Ba/F3-EGFR-insSVD.

For cell survival assays, Ba/F3 cells were grown to a density of 1-2million cells per mL, spun down and resuspended in media without IL-3,and replated at a concentration 200,000-500,000 cells per mL. The cellsectopically expressing WT EGFR were plated with 10 ng/mL MilliporeCulture grade EGF. The cells ectopically expressing EGFR-insSVD wereplated without EGF.

24 hours later, cells were plated in 30 μL in a 384 well plate at aconcentration of 3200 cells per well for cells assayed in the absence ofIL-3. 100 nL of compound was added to each well using a 100 nL pin head,and plates were incubated at 37° C. for 48 h.

Cell viability was measured by adding 30 μL of Cell Titer-GloLuminescent Cell Viability Reagent. Plates were sealed with Perkin ElmerTop-Seal, inverted several times to mix, and immediately centrifuged at1000 rpm for 2 min. Plates were incubated in low light conditions for8-10 min and luminescence was measured.

Table 10 shows the results of the inhibition in proliferation assaysperformed in BA/F3 (ins SVD) and BA/F3 (wild type) cell lines (IC₅₀ isthe concentration for 50% of maximal inhibition of cell proliferation).

TABLE 10 BA/F3 (insSVD) BA/F3 (wild type) Example IC₅₀ IC₅₀ No. [mol/l][mol/l] 1 2.74E−7 4.81E−7 2 8.81E−9 1.87E−6 7.48E−9 <4.78E−9 6.80E−97.49E−9 3 5.87E−7 2.16E−6 4 3.29E−7 1.61E−6 5 5.67E−7 6 6.33E−8 3.94E−77 4.62E−7 2.70E−6 8 6.95E−8 6.23E−7 9 1.21E−7 3.76E−7 10 5.69E−8 3.52E−711 3.57E−7 1.78E−6 12 13 8.11E−7 4.01E−6 14 1.04E−6 2.53E−6 15 4.09E−72.87E−6 16 2.41E−8 4.54E−7 17 1.19E−8 3.97E−7 18 1.80E−7 2.45E−6 194.01E−8 8.70E−7 20 4.83E−8 6.25E−7 21 8.81E−9 2.51E−7 7.48E−9 <4.78E−96.80E−9 7.49E−9 22 1.16E−7 1.56E−6 23 3.30E−8 3.88E−7 24 25 8.42E−72.28E−6 8.72E−7 >2.00E−6 7.71E−7 7.41E−7 26 6.18E−7 2.00E−6 27 4.98E−72.50E−6 28 6.44E−7 3.67E−6 29 2.29E−7 2.36E−6 30 1.49E−7 1.86E−6 311.58E−7 1.71E−6 32 9.87E−9 2.99E−7 33 9.32E−9 4.76E−7 34 7.00E−9 2.78E−735 7.98E−9 4.28E−7 36 9.55E−9 5.29E−7 37 1.60E−8 5.83E−7 38 1.75E−84.66E−7 39 2.75E−8 6.61E−7 40 5.05E−8 1.45E−6 41 5.25E−8 7.95E−7 427.29E−8 6.25E−7 43 1.17E−7 1.88E−6 44 1.73E−7 2.45E−6 45 2.55E−7 2.49E−646 1.51E−8 3.64E−7 47 4.48E−7 3.24E−6 48 5.59E−9 2.76E−7 49 1.91E−89.19E−7 50 6.09E−8 2.10E−6 51 1.07E−7 3.29E−6 52 2.91E−8 8.34E−7 533.11E−8 8.04E−7 54 3.75E−8 1.30E−6 55 3.03E−7 2.83E−6 56 2.42E−7 1.90E−657 1.47E−8 5.35E−7 58 1.86E−8 5.61E−7 59 1.77E−8 5.42E−7 60 3.86E−81.75E−6 61 8.89E−8 1.46E−6 62 1.66E−7 2.76E−6 63 1.23E−8 4.85E−7 641.21E−7 1.89E−6 65 1.43E−7 2.26E−6 66 4.60E−9 1.53E−7 67 9.33E−9 2.84E−768 2.94E−9 1.09E−7 69 1.24E−8 2.90E−7 70 1.61E−8 2.97E−7 71 2.02E−87.81E−7 72 6.77E−8 1.01E−6 73 4.16E−7 2.52E−6 74 9.79E−8 4.07E−6 759.80E−8 2.36E−6 76 2.50E−7 2.09E−6 77 4.63E−8 1.48E−6 78 1.60E−8 5.83E−779 1.18E−7 1.81E−6 80 2.06E−7 1.46E−6 81 4.05E−7 4.19E−6 82 9.09E−78.61E−6 83 1.00E−7 2.29E−6 84 1.88E−7 2.21E−6 85 5.01E−76.57E−6 >2.00E−5 86 1.28E−8 3.77E−7 87 3.44E−8 1.06E−6 88 3.80E−83.88E−7 89 1.28E−8 2.52E−7 90 2.90E−8 2.66E−6 91 3.57E−8 1.10E−6 921.04E−8 3.09E−7 93 4.68E−7 3.68E−6 94 5.49E−8 4.62E−6 95 1.41E−7 2.37E−696 4.96E−8 1.47E−6

Compounds of the present invention may show additional advantageousproperties, such as, more potent inhibition of mutant EGFR with exon 20insertions than inhibition of wild-type EGFR, which may be useful toreduce potential toxicity arising from excessive inhibition of wild-typeEGFR. Surprisingly, we found that the claimed compounds arebiochemically highly potent and show a >5-fold selectivity on EGFR exon20 insertions versus wild-type EGFR in anti-proliferative assays. Thisfinding clearly supports improved feasibility of the here describedcompounds for a novel, efficacious and more tolerable therapy for EGFRexon 20 insertion patients.

In contrast to the claimed compounds of this invention the compoundsclaimed in the closest prior art WO2016/120196 do not show theadvantageous combined properties described above. This can be seen inTable 11.

TABLE 11 mutEGFR (D770_N771insSVD) BA/F3 BA/F3 kinase assay (insSVD)(wild type) WO2016/120196 IC₅₀ IC₅₀ IC₅₀ Example No. [mol/l] [mol/l][mol/l] 38 2.24E−7 >2.00E−6 5.91E−6 41 3.43E−8 >2.00E−6 5.02E−6 451.28E−8 >2.00E−6 4.04E−6

REFERENCES

-   Pao et al, 2010: Pao and Chmielecki, Nat Rev Cancer. 2010 November;    10(11):760-74-   Paez et al, 2004: Paez et al., Science. 2004 Jun. 4;    304(5676):1497-500-   Mok et al, 2009: Mok et al., N Engl J Med. 2009 Sep. 3;    361(10):947-57-   Sequist et al, 2013: Sequist et al., J Clin Oncol. 2013 Sep. 20;    31(27):3327-34-   Pao et al, 2005: Pao et al., PLoS Med. 2005 March; 2(3):e73-   Mok et al, 2017: Mok et al., N Engl J Med. 2017 Feb. 16;    376(7):629-640-   Yasuda, 2013: Yasuda, Sci Transl Med. 2013 Dec. 18; 5(216):216ra177-   Chen et al, 2016: Chen et al., Onco Targets Ther. 2016 Jul. 8;    9:4181-6-   Yang et al, 2015: Yang et al., Lancet Oncol. 2015 July; 16(7):830-8-   Hasako et al., 2018: Hasako et al., Mol Cancer Ther. 2018 August;    17(8): 1648-1658-   Jang et al., 2018: Jang et al., Angew Chem Int Ed Engl. 2018 Sep. 3;    57(36)-   Floc'h et al., 2018: Floc'h et al., Mol Cancer Ther. 2018 May 17(5):    885-896-   Robichaux et al., 2018: Robichaux et al., Nat Med. 2018 May;    24(5):638-646-   Doebele et al., 2018: Doebele et al., Poster 338, presented at the    54th Annual Meeting of the American Society of Clinical Oncology,    Jun. 1-5, 2018, Chicago, Ill.-   Oxnard et al, 2013: Oxnard et al., J Thorac Oncol. 2013 February;    8(2): 179-184

The invention claimed is:
 1. A compound of formula (I)

in which: R¹ represents methyl, ethyl, trifluoromethyl,2,2-difluoroethyl, cyano, bromo, methoxy, or difluoromethoxy, or withthe proviso that when R¹ is chloro, then R² represents hydrogen orchloro and R³ and R⁴ represent hydrogen; R² represents hydrogen, methyl,fluoro, chloro or bromo; R³ represents hydrogen or fluoro; R⁴ representshydrogen or fluoro, wherein at least one of R³ and R⁴ representshydrogen; R⁵ represents C₂-C₅-alkyl, which is substituted once withhydroxy, C₁-C₄-alkoxy, R⁷R⁸N—, or phenyl, or R⁶—CH₂—, wherein saidphenyl groups are optionally substituted one or more times,independently of each other, with R; R′ represents, independently ofeach other, hydroxy, halogen, cyano, C₁-C₄-alkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkyl or C₁-C₄-haloalkoxy; R⁶ represents a group selected fromthe group:

wherein * indicates the point of attachment of said group with the restof the molecule; R⁷, R⁸ represent, independently of each other,C₁-C₃-alkyl, C₁-C₃-haloalkyl or R⁷ and R⁸ together with the nitrogenatom to which they are attached form a 5- to 6-membered nitrogencontaining heterocyclic ring, optionally containing one additionalheteroatom or heteroatom containing group selected from O and NR¹⁰; R⁹represents hydrogen, C₁-C₃-alkyl or C₁-C₃-haloalkyl; R¹⁰ representshydrogen or C₁-C₃-alkyl; or an N-oxide, a salt, a tautomer or astereoisomer of said compound, or a salt of said N-oxide, tautomer orstereoisomer.
 2. The compound of formula (I) according to claim 1,wherein: R¹ represents methyl, ethyl, trifluoromethyl,2,2-difluoroethyl, cyano, bromo, methoxy, or difluoromethoxy, or withthe proviso that when R¹ is chloro, then R² represents; R² representsfluoro or chloro; R³ represents hydrogen; R⁴ represents hydrogen; R⁵represents C2-C₅-alkyl, which is substituted once with hydroxy,C₁-C₂-alkoxy or R⁷R⁸N—, or R⁶—CH₂—; R⁶ represents a group selected fromthe group:

wherein * indicates the point of attachment of said group with the restof the molecule; R⁷, R⁸ represent, independently of each other,C₁-C₂-alkyl, or C₁-C₂-haloalkyl; R⁹ represents hydrogen, C₁-C₂-alkyl orC₁-C₂-haloalkyl; or an N-oxide, a salt, a tautomer or a stereoisomer ofsaid compound, or a salt of said N-oxide, tautomer or stereoisomer. 3.The compound of formula (I) according to claim 1, wherein: R¹ representsmethyl, ethyl, trifluoromethyl, 2,2-difluoroethyl, cyano, bromo,methoxy, or difluoromethoxy, or with the proviso that when R¹ is chloro,then R² represents chloro; R² represents fluoro or chloro; R³ representshydrogen; R⁴ represents hydrogen; R⁵ represents C₄-C₅-alkyl, which issubstituted once with hydroxy, methoxy or R⁷R⁸N—, or R⁶—CH₂—; R⁶represents a group selected from the group:

wherein * indicates the point of attachment of said group with the restof the molecule; R⁷, R⁸ represent, independently of each other, methyl,or C₁-C₂-fluoroalkyl; R⁹ represents C₁-C₂-alkyl or C₁-C₂-fluoroalkyl; oran N-oxide, a salt, a tautomer or a stereoisomer of said compound, or asalt of said N-oxide, tautomer or stereoisomer.
 4. The compound offormula (I) according to claim 1, which is selected from the groupconsisting of:3-{[2-(difluoromethoxy)phenyl]amino}-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-[(2-bromo-3-fluorophenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one2-[3-(2-methoxyethoxy)pyridin-4-yl]-3-[(2-methoxyphenyl)amino]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-{[2-(2,2-difluoroethyl)phenyl]amino}-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-fluoro-2-methoxyanilino)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-fluoro-2-methoxyanilino)-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-[2-(difluoromethoxy)-3-fluoroanilino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-[2-(difluoromethoxy)-3-fluoroanilino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-[(3-fluoro-2-methylphenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-fluoro-2-methylanilino)-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-{[2-(2,2-difluoroethyl)-3-fluorophenyl]amino}-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-[2-(2,2-difluoroethyl)-3-fluoroanilino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-[(3,4-difluoro-2-methoxyphenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-[(3,4-difluoro-2-methoxyphenyl)amino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-[(3,5-difluoro-2-methoxyphenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3,5-difluoro-2-methoxyanilino)-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-chloro-2-methoxyanilino)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-chloro-2-methoxyanilino)-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(2,3-dichloroanilino)-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(2-ethyl-3-fluoroanilino)-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-chloro-2-methylanilino)-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(2-bromo-3-fluoroanilino)-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-[3-chloro-2-(difluoromethoxy)anilino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(2-chloroanilino)-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3,5-difluoro-2-methylanilino)-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-[3-fluoro-2-(trifluoromethyl)anilino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-3-[2-(trifluoromethyl)anilino]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-[2-(difluoromethoxy)-3,5-difluoroanilino]-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-chloro-4-fluoro-2-methoxyanilino)-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(5-fluoro-2-methylanilino)-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(2,3-dichloroanilino)-2-[3-(2-methoxyethoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one2-[3-(2-methoxyethoxy)pyridin-4-yl]-3-[2-(trifluoromethyl)anilino]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-fluoro-2-methylanilino)-2-(3-{[(2S)-1-methyl pyrrol i din-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-[3-chloro-2-(difluoromethoxy)anilino]-2-(3-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3,5-difluoro-2-methylanilino)-2-(3-{[(2S)-1-methyl pyrrol idin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-chloro-2-methylanilino)-2-{3-[2-(dimethylamino)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one2-{3-[2-(dimethylamino)ethoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-chloro-2-methoxyanilino)-2-{3-[2-(dimethylamino)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3,5-difluoro-2-methylanilino)-2-{3-[2-(dimethylamino)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one2-{3-[2-(dimethylamino)ethoxy]pyridin-4-yl}-3-(3-fluoro-2-methylanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-fluoro-2-methoxyanilino)-2-[3-(3-methoxy-3-methylbutoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one2-[3-(2-ethoxy-2-methylpropoxy)pyridin-4-yl]-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-chloro-2-methoxyanilino)-2-[3-(2-hydroxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-chloro-2-methylanilino)-2-{3-[2-(dimethylamino)-2-methylpropoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one2-{3-[2-(dimethylamino)-2-methylpropoxy]pyridin-4-yl}-3-(3-fluoro-2-methylanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3,5-difluoro-2-methylanilino)-2-{3-[2-(dimethylamino)-2-methylpropoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-chloro-2-methoxyanilino)-2-(3-{[l-methylpiperidin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-[2-(difluoromethoxy)-3-fluoroanilino]-2-{3-[2-(dimethylamino)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-fluoro-2-methylanilino)-2-(3-{[oxolan-3-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-oxolan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-chloro-2-methoxyanilino)-2-(3-{[(2R)-oxolan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-chloro-2-methoxyanilino)-2-{3-[(oxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(2,3-dichloroanilino)-2-{3-[(oxan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(2,3-dichloroanilino)-2-(3-{[(2S)-oxolan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(2,3-dichloroanilino)-2-(3-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-fluoro-2-methoxyanilino)-2-[3-(2-hydroxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-[2-(difluoromethoxy)-3-fluoroanilino]-2-[3-(2-hydroxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one2-{3-[2-(dimethylamino)-2-methylpropoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-fluoro-2-methoxyanilino)-2-{3-[2-methyl-2-(morpholin-4-yl)propoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-[2-(difluoromethoxy)-3-fluoroanilino]-2-{3-[2-methyl-2-(morpholin-4-yl)propoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-chloro-2-methylanilino)-2-(3-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(2-bromo-3-chloroanilino)-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-[3-chloro-2-(difluoromethoxy)anilino]-2-{3-[(oxolan-3-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-pyrrolidin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-[3-chloro-2-(difluoromethoxy)anilino]-2-{3-[2-(morpholin-4-yl)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-[3-chloro-2-(difluoromethoxy)anilino]-2-{3-[(oxan-4-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-{[2-(difluoromethoxy)-3-fluorophenyl]amino}-2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-onehydrochloride 3-(3-fluoro-2-m ethoxyanilino)-2-{3-[2-(morpholin-4-yl)ethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one2-{3-[2-(diethylamino)ethoxy]pyridin-4-yl}-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-fluoro-2-methoxyanilino)-2-{3-[(oxolan-2-yl)methoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one2-[3-(2-tert-butoxyethoxy)pyridin-4-yl]-3-(3-chloro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-fluoro-2-m ethoxyanilino)-2-(3-{[(2S)-oxolan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-fluoro-2-methoxyanilino)-2-(3-{[(2R)-oxolan-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-fluoro-2-m ethoxyanilino)-2-(3-{[1-methylpiperidin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one2-[3-(2-tert-butoxyethoxy)pyridin-4-yl]-3-(3-fluoro-2-methoxyanilino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-fluoro-2-methoxyanilino)-2-{3-[(2R)-2-methoxypropoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-fluoro-2-methoxyanilino)-2-(3-{[l-phenylpropan-2-yl]oxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one2-fluoro-6-({2-[3-(2-methoxy-2-methylpropoxy)pyridin-4-yl]-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-3-yl}amino)benzonitrile3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl]methoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one3-(3-chloro-4-fluoro-2-methoxyanilino)-2-(3-{2-[methyl(2,2,2-trifluoroethyl)amino]ethoxy}pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-oneor an N-oxide, a salt, a tautomer or a stereoisomer of said compound, ora salt of said N-oxide, tautomer or stereoisomer.
 5. A pharmaceuticalcomposition comprising at least one compound of general formula (I)according to claim 1, together with at least one pharmaceuticallyacceptable auxiliary.
 6. The composition according to claim 5 for thetreatment of haematological tumours, solid tumours and/or metastasesthereof.
 7. A combination comprising one or more first activeingredients selected from a compound of general formula (I) according toclaim 1, and one or more chemotherapeutic anti-cancer agents.
 8. Amethod for the treatment or prophylaxis of disease of a subjectcomprising administration of a compound of general formula (I) accordingto claim 1 to the subject: wherein the disease comprises uncontrolledcell growth, proliferation, and/or survival, inappropriate cellularimmune responses, or inappropriate inflammatory responses mediated by anEGF-receptor having a mutation in exon
 20. 9. A method of inhibitingEGF-receptor kinase activity in a cancer cell comprising an EGF-receptorhaving a mutation in exon 20, the method comprising contacting thecancer cell with a compound of general formula (I) according to claim 1.10. A method of reducing the survival of a cancer cell or inducing deathin a cancer cell, the method comprising contacting a cancer cellcomprising an EGF-receptor having a mutation in exon 20 with a compoundof general formula (I) according to claim
 1. 11. A method of enhancingthe efficacy of an anti-EGF-receptor therapy, the method comprisingadministering to the subject an anti-EGF receptor therapy in combinationwith a compound of general formula (I) according to claim
 1. 12. Amethod of treating cancer in a subject, wherein the cancer is or hasacquired resistance to an anti-EGF receptor therapy, the methodcomprising administering to the subject an effective amount of acompound of general formula (I) according to claim
 1. 13. A method fortreating a patient with cancer, the method comprising administering tothe subject an anti-EGF receptor therapy in combination with a compoundof general formula (I) according to claim 1, wherein the subject isselected for therapy by detecting the presence of a mutation in exon 20of the EGF-receptor in a biological sample of the subject.
 14. A methodof treating cancer comprising an EGF-receptor having a mutation in exon20 in a subject, the method comprising administering to the subject aneffective amount of a compound of general formula (I) according toclaim
 1. 15. The method of claim 14, wherein the cancer is selected fromthe group consisting of leukemia, myelodysplastic syndrome, malignantlymphoma, head and neck tumours, tumours of the thorax, gastrointestinaltumours, endocrine tumours, mammary and other gynaecological tumours,urological tumours, skin tumours, and sarcomas.
 16. The method of claim15, wherein the cancer is selected from the group consisting of invertedsinonasal papilloma or inverted sinonasal papilloma associatedsinanonasal squamous cell carcinoma.
 17. The method of claim 14, whereinthe EGF-receptor comprises an insertion in exon
 20. 18. The method ofclaim 17, wherein the EGF-receptor comprises an insertion between aminoacids V769-D770 and/or between amino acids D770-N771.
 19. The method ofclaim 15, wherein the tumour of the thorax is non-small cell lungcancer.